Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man

  • Maurice J. ArnaudEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 200)


Caffeine, theophylline, theobromine, and paraxanthine administered to animals and humans distribute in all body fluids and cross all biological membranes. They do not accumulate in organs or tissues and are extensively metabolized by the liver, with less than 2% of caffeine administered excreted unchanged in human urine. Dose-independent and dose-dependent pharmacokinetics of caffeine and other dimethylxanthines may be observed and explained by saturation of metabolic pathways and impaired elimination due to the immaturity of hepatic enzyme and liver diseases. While gender and menstrual cycle have little effect on their elimination, decreased clearance is seen in women using oral contraceptives and during pregnancy. Obesity, physical exercise, diseases, and particularly smoking and the interactions of drugs affect their elimination owing to either stimulation or inhibition of CYP1A2. Their metabolic pathways exhibit important quantitative and qualitative differences in animal species and man. Chronic ingestion or restriction of caffeine intake in man has a small effect on their disposition, but dietary constituents, including broccoli and herbal tea, as well as alcohol were shown to modify their plasma pharmacokinetics. Using molar ratios of metabolites in plasma and/or urine, phenotyping of various enzyme activities, such as cytochrome monooxygenases, N-acetylation, 8-hydroxylation, and xanthine oxidase, has become a valuable tool to identify polymorphisms and to understand individual variations and potential associations with health risks in epidemiological surveys.


Absorption Age Alcohol Bioavailability Caffeine Cytochromes Diet Diseases Distribution Drugs Excretion Gender Hormones Interactions Metabolism Obesity Paraxanthine Pharmacokinetics Physical exercise Smoking Theobromine Theophylline 





1,3,7-Trimethyluric acid


1,3-Dimethyluric acid




1,7-Dimethyluric acid


1-Methyluric acid






3,7-Dimethyluric acid


3-Methyluric acid




7-Methyluric acid








Area under the concentration versus time curve


Peak plasma concentration


Cytochrome P450




Ideal body weight


Absorption rate constant


Elimination rate constant


Michaelis–Menten constant


N-Acetyltransferase 2


Total body weight


Time to reach the peak plasma concentration


  1. Abdi F, Pollard I, Wilkinson J (1993) Placental transfer and foetal disposition of caffeine and its immediate metabolites in the 20-day pregnant rat: function of dose. Xenobiotica 23(4):449–456PubMedCrossRefGoogle Scholar
  2. Abernethy D, Todd E (1985) Impairment of caffeine clearance by chronic use of low-dose estrogen-containing oral contraceptives. Eur J Clin Pharmacol 28(4):425–428PubMedCrossRefGoogle Scholar
  3. Abernethy DR, Todd EL, Schwartz JB (1985) Caffeine disposition in obesity. Br J Clin Pharmacol 20(1):61–66PubMedCrossRefGoogle Scholar
  4. Aldridge A, Neims AH (1979) The effects of phenobarbital and beta-naphthoflavone on the elimination kinetics and metabolite pattern of caffeine in the beagle dog. Drug Metab Dispos 7(6):378–382PubMedGoogle Scholar
  5. Aldridge A, Neims AH (1980) Relationship between the clearance of caffeine and its 7-N-demethylation in developing beagle puppies. Biochem Pharmacol 29(3):1909–1914PubMedCrossRefGoogle Scholar
  6. Amchin J, Zarycranski W, Taylor KP, Albano D, Klockowski PM (1999) Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine. J Clin Pharmacol 39(3):252–259PubMedGoogle Scholar
  7. Amodio P, Lauro S, Rondana M, Crema G, Merkel C, Gatta A, Ruol A (1991) Theophylline pharmacokinetics and liver function indexes in chronic liver disease. Respiration 58(2):106–111PubMedCrossRefGoogle Scholar
  8. Anonymous (1991) International Agency for Research on Cancer (IARC) monographs on the evaluation of carcinogenic risks to humans, WHO, vol 51. Coffee, tea, maté, methylxanthines and methylglyoxal. WHO, Geneva, p 513Google Scholar
  9. Aranda JV, Louridas AT, Vitullo BB, Thom P, Aldridge A, Haber R (1979) Metabolism of theophylline to caffeine in human fetal liver. Science 206(4424):1319–1321PubMedCrossRefGoogle Scholar
  10. Arimori K, Nakano M (1988) Dose-dependency in the exsorption of theophylline and the intestinal dialysis of theophylline by oral activated charcoal in rats. J Pharm Pharmacol 40(2):101–105PubMedCrossRefGoogle Scholar
  11. Arnaud MJ (1976) Identification, kinetic and quantitative study of [2-14C] and [1-Me-14C] caffeine metabolites in rat’s urine by chromatographic separations. Biochem Med 16(1):67–76PubMedCrossRefGoogle Scholar
  12. Arnaud MJ (1980) Metabolism of labeled paraxanthine in the rat: comparison of rat and human metabolic pathway. Nutr Rev 38(5):196–200Google Scholar
  13. Arnaud MJ (1983) The effect of dietary factors on the bioavailability of methylxanthines. Proceedings of the toxicology forum, Aspen, Colorado, pp 234–243Google Scholar
  14. Arnaud MJ (1984) Products of metabolism of caffeine. In: Dews PB (ed) caffeine. Springer, Berlin, pp 3–38CrossRefGoogle Scholar
  15. Arnaud MJ (1985) Comparative metabolic disposition of [1-Me14C] caffeine in rats, mice, and Chinese hamsters. Drug Metab Dispos 13(4):471–478PubMedGoogle Scholar
  16. Arnaud MJ (1987) The pharmacology of caffeine. Prog Drug Res 31:273–313PubMedGoogle Scholar
  17. Arnaud MJ (1988) The metabolism of coffee constituents in coffee, vol 3. In: Clarke RJ, Macrae R (eds) Physiology. Elsevier, London, pp 33–55Google Scholar
  18. Arnaud MJ (1993a) Metabolism of caffeine and other components of coffee. In: Garattini S (ed) Caffeine coffee and health. Raven, New York, pp 43–95Google Scholar
  19. Arnaud MJ (1993b) Caffeine, vol 1. In: Macrae R, Robinson RK, Sadler MJ (eds) Encyclopaedia of food science, food technology and nutrition. Academic, London, pp 566–571Google Scholar
  20. Arnaud MJ (1998) Pharmacokinetics and metabolism of caffeine. In: Snel J, Lorist MM (eds) Nicotine, caffeine and social drink, behaviour and brain function. Harwood, Amsterdam, pp 153–165Google Scholar
  21. Arnaud MJ, Ben Zvi Z, Yaari A, Gorodischer R (1986a) 1,3,8-Trimethylallantoin: a major caffeine metabolite formed by rat liver. Res Commun Chem Pathol Pharmacol 52(3):407–410PubMedGoogle Scholar
  22. Arnaud MJ, Bracco I (1981) Distribution and metabolism of theophylline in the pregnant rat: presence of a blood brain barrier. Experientia 37(6):665Google Scholar
  23. Arnaud MJ, Bracco I, Getaz F (1989) Synthesis of ring labelled caffeine for the study of metabolic and pharmacokinetics mouse interstrain differences in relation to pharmacologic and toxic effects. In: Baillie TA, Jones JR (eds) Synthesis and applications of isotopically labelled compounds. Elsevier, Amsterdam, pp 645–648Google Scholar
  24. Arnaud MJ, Bracco I, Sauvageat JL, Clerc MF (1983) Placental transfer of the major caffeine metabolite in the rat using 6-amino-5[N-formylmethylamino]1, 3[Me-14C]-dimethyluracil administered orally or intravenously to the pregnant rat. Toxicol Lett 16(3–4):271–279PubMedCrossRefGoogle Scholar
  25. Arnaud MJ, Bracco I, Welsch C (1982a) Metabolism and distribution of labeled theophylline in the pregnant rat. Impairment of theophylline metabolism by pregnancy and absence of a blood-brain barrier in the fetus. Pediatr Res 16(3):167–171PubMedCrossRefGoogle Scholar
  26. Arnaud MJ, Enslen M (1992) The role of paraxanthine in mediating physiological effects of caffeine. In: 14th international conference in coffee science, San Francisco, 14–19 July 1991. Proceedings ASIC, Paris, pp 71–79Google Scholar
  27. Arnaud MJ, Gétaz F (1982) Postnatal establishment of a blood-brain barrier for theobromine in the rat. Experientia 38(6):752Google Scholar
  28. Arnaud MJ, Gétaz F (1983) Theobromine distribution in the pregnant rat and the fetus and the impairment of its metabolism due to pregnancy. Experientia 39(6):678Google Scholar
  29. Arnaud MJ, Richli U, Philippossian G (1986b) Isolation and identification of paraxanthine glucuronide as the major caffeine metabolite in mice. Experientia 42(6):696Google Scholar
  30. Arnaud MJ, Thelin-Doerner A, Ravussin E, Acheson KJ (1980) Study of the demethylation of [1,3,7-Me-13C] caffeine in man using respiratory exchange measurements. Biomed Mass Spectrom 7(11–12):521–524PubMedCrossRefGoogle Scholar
  31. Arnaud MJ, Welsch C (1979a) Metabolic pathway of theobromine in the rat and identification of two new metabolites in human urine. J Agric Food Chem 27(3):524–527PubMedCrossRefGoogle Scholar
  32. Arnaud MJ, Welsch C (1979b) Metabolism of [1-Me-14C] paraxanthine in the rat: identification of a new metabolite. Experientia 35(7):946Google Scholar
  33. Arnaud MJ, Welsch C (1980a) Caffeine metabolism in human subjects. In: Proceedings of the ninth international colloquium on science and technology of coffee. Association Scientifique Internationale du Cafe, London, pp 385–395Google Scholar
  34. Arnaud MJ, Welsch C (1980b) Quantitative analysis of theophylline metabolites by HPLC, after oral or i.v. administration. Experientia 36(6):704Google Scholar
  35. Arnaud MJ, Welsch C (1982) Theophylline and caffeine metabolism in man. In: Woodcock BG, Staib AH, Rietbrock N (eds) Methods in clinical pharmacology, 3: theophylline and other methylxanthines. Vieweg, Brunswick, pp 135–148Google Scholar
  36. Arnaud MJ, Wietholtz H, Voegelin M, Bircher J, Preisig R (1982b) Assessment of the cytochrome P-448 dependent liver enzyme system by a caffeine breath test. In: Sato R (ed) Microsomes drug oxidation and drug toxicity. Wiley, New York, pp 443–444Google Scholar
  37. Arold G, Donath F, Maurer A, Diefenbach K, Bauer S, Henneicke-von Zepelin HH, Friede M, Roots I (2005) No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John’s wort extract. Planta Med 71(4):331–337PubMedCrossRefGoogle Scholar
  38. Azcona O, Barbanoj MJ, Torrent J, Jané F (1995) Evaluation of the central effects of alcohol and caffeine interaction. Br J Clin Pharmacol 40(4):393–400PubMedCrossRefGoogle Scholar
  39. Backman JT, Karjalainen MJ, Neuvonen M, Laitila J, Neuvonen PJ (2006) Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol 62(3):345–357PubMedCrossRefGoogle Scholar
  40. Bapiro TE, Sayi J, Hasler JA, Jande M, Rimoy G, Masselle A, Masimirembwa CM (2005) Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans. Eur J Clin Pharmacol 61(10):755–761PubMedCrossRefGoogle Scholar
  41. Bayar C, Ozer I (1997) A study on the route of 1-methylurate formation in theophylline metabolism. Eur J Drug Metab Pharmacokinet 22(4):415–419PubMedCrossRefGoogle Scholar
  42. Bchir F, Dogui M, Ben Fradj R, Arnaud MJ, Saguem S (2006) Differences in pharmacokinetic and electroencephalographic responses to caffeine in sleep-sensitive and non-sensitive subjects. C R Biol 329(7):512–519PubMedCrossRefGoogle Scholar
  43. Beach CA, Mays DC, Sterman BM, Gerber N (1985) Metabolism, distribution, seminal excretion and pharmacokinetics of caffeine in the rabbit. J Pharmacol Exp Ther 233(1):18–23PubMedGoogle Scholar
  44. Becker AB, Simons KJ, Gillespie CA, Simons FE (1984) The bronchodilator effects and pharmacokinetics of caffeine in asthma. N Engl J Med 310(12):743–746PubMedCrossRefGoogle Scholar
  45. Begas E, Kouvaras E, Tsakalof A, Papakosta S, Asprodini EK (2007) In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios. Biomed Chromatogr 21(2):190–200PubMedCrossRefGoogle Scholar
  46. Benowitz NL, Jacob P 3rd, Mayan H, Denaro C (1995) Sympathomimetic effects of paraxanthine and caffeine in humans. Clin Pharmacol Ther 58(6):684–691PubMedCrossRefGoogle Scholar
  47. Berdel D, Süverkrüp R, Heimann G, von Berg A, Liappis N, Stühmer A (1987) Total theophylline clearance in childhood: the influence of age-dependent changes in metabolism and elimination. Eur J Pediatr 146(1):41–43PubMedCrossRefGoogle Scholar
  48. Bienvenu T, Pons G, Rey E, Richard MO, d'Athis P, Arnaud MJ, Olive G (1990) Effect of growth hormone on caffeine metabolism in hypophysectomized rats. Drug Metab Dispos 18(3):327–330PubMedGoogle Scholar
  49. Birkett DJ, Miners JO, Attwood J (1983) Secondary metabolism of theophylline biotransformation products in man-route of formation of 1-methyluric acid. Br J Clin Pharmacol 15(1):117–119PubMedCrossRefGoogle Scholar
  50. Birkett DJ, Dahlqvist R, Miners JO, Lelo A, Billing B (1985) Comparison of theophylline and theobromine metabolism in man. Drug Metab Dispos 13(6):725–728PubMedGoogle Scholar
  51. Birkett DJ, Miners JO (1991) Caffeine renal clearance and urine caffeine concentrations during steady state dosing Implications for monitoring caffeine intake during sport events. Br J Clin Pharmacol 31(4):405–408PubMedCrossRefGoogle Scholar
  52. Blake MJ, Abdel-Rahman SM, Pearce RE, Leeder JS, Kearns GL (2006) Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Pediatr Res 60(6):717–723PubMedCrossRefGoogle Scholar
  53. Blanchard J, Sawers SJA (1983a) The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol 24(1):93–98PubMedCrossRefGoogle Scholar
  54. Blanchard J, Sawers SJA (1983b) Comparative pharmacokinetics of caffeine in young and elderly men. J Pharmacokinet Biopharm 11(2):109–126PubMedCrossRefGoogle Scholar
  55. Blanchard J, Sawers SJ (1983c) Relationship between urine flow rate and renal clearance of caffeine in man. J Clin Pharmacol 23(4):134–138PubMedGoogle Scholar
  56. Blanchard J, Sawers SJA, Jonkman JHG, Tang-Liu D-S (1985) Comparison of the urinary metabolite profile of caffeine in young and elderly males. Br J Clin Pharmacol 19(2):225–232PubMedCrossRefGoogle Scholar
  57. Blanchard J, Harvey S, Morgan WJ (1992) Relationship between serum and saliva theophylline levels in patients with cystic fibrosis. Ther Drug Monit 14(1):48–54PubMedCrossRefGoogle Scholar
  58. Bologa M, Tang B, Klein J, Tesoro A, Koren G (1991) Pregnancy-induced changes in drug metabolism in epileptic women. J Pharmacol Exp Ther 257(2):735–740PubMedGoogle Scholar
  59. Bonati M, Latini R, Galletti F, Young JF, Tognoni G, Garattini S (1982) Caffeine disposition after oral doses. Clin Pharmacol Ther 32(1):98–106PubMedCrossRefGoogle Scholar
  60. Bonati M, Latini R, Sadurska B, Riva E, Galletti F, Borzelleca JF, Tarka SM, Arnaud MJ, Garattini S (1984) Kinetics and metabolism of theobromine in male rats. Toxicology 30(4):327–341PubMedCrossRefGoogle Scholar
  61. Bortolotti A, Jiritano L, Bonati M (1985) Pharmacokinetics of paraxanthine, one of the primary metabolites of caffeine, in the rat. Drug Metab Dispos 13(2):227–231PubMedGoogle Scholar
  62. Bory C, Baltassat P, Porthault M, Bethenod M, Frederich A, Aranda JV (1979) Metabolism of theophylline to caffeine in premature newborn infants. J Pediatr 94(6):988–993PubMedCrossRefGoogle Scholar
  63. Boutroy MJ, Vert P, Monin P, Royer RJ, Royer-Morrot MJ (1979) Methylation of theophylline to caffeine in premature infants. Lancet 14(8120):830CrossRefGoogle Scholar
  64. Bracco D, Ferrarra J-M, Arnaud MJ, Jequier E, Schutz Y (1995) Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women. Am J Physiol 269(4 Pt 1):E671–E678PubMedGoogle Scholar
  65. Brachtel D, Richter E (1988) Effect of altered gastric emptying on caffeine absorption. Z Gastroenterol 26(5):245–251PubMedGoogle Scholar
  66. Brandstetter Y, Kaplanski J, van Creveld C, Ben-Zvi Z (1986) Theophylline pharmacokinetics in pregnant and lactating rats. Res Commun Chem Pathol Pharmacol 53(2):269–272PubMedGoogle Scholar
  67. Brazier JL, Descotes J, Lery N, Ollagnier M, Evreux JC (1980a) Inhibition by idrocilamide of the disposition of caffeine. Eur J Clin Pharmacol 17(1):37–43PubMedCrossRefGoogle Scholar
  68. Brazier JL, Ribon B, Desage M, Salle B, Salle B (1980b) Study of theophylline metabolism in premature human newborns using stable isotope labelling. Biomed Mass Spectrom 7(5):189–192PubMedCrossRefGoogle Scholar
  69. Brøsen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S (1993) Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45(6):1211–1214PubMedCrossRefGoogle Scholar
  70. Brouwers J, Ingels F, Tack J, Augustijns P (2005) Determination of intraluminal theophylline concentrations after oral intake of an immediate- and a slow-release dosage form. J Pharm Pharmacol 57(8):987–996PubMedCrossRefGoogle Scholar
  71. Brown CR, Benowitz NL (1989) Caffeine and cigarette smoking: behavioral, cardiovascular, and metabolic interactions. Pharmacol Biochem Behav 34(3):565–570PubMedCrossRefGoogle Scholar
  72. Brown CR, Jacob P 3rd, Wilson M, Benowitz NL (1988) Changes in rate and pattern of caffeine metabolism after cigarette abstinence. Clin Pharmacol Ther 43(5):488–491PubMedCrossRefGoogle Scholar
  73. Bruguerolle B (1987) [Changes in the pharmacokinetics of theophylline during estrus in rats]. Pathol Biol 35(2):181–183PubMedGoogle Scholar
  74. Butler MA, Lang NP, Young JF, Caporaso NE, Vineis P, Hayes RB, Teitel CH, Massengill JP, Lawsen MF, Kadlubar FF (1992) Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 2(3):116–127PubMedCrossRefGoogle Scholar
  75. Callahan MM, Robertson RS, Arnaud MJ, Branfman AR, McComish MF, Yesair DW (1982) Human metabolism of [1-methyl-14C]- and [2-14C]caffeine after oral administration. Drug Metab Dispos 10(4):417–423PubMedGoogle Scholar
  76. Campbell ME, Grant DM, Inaba T, Kalow W (1987a) Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes. Drug Metab Dispos 15(2):237–249PubMedGoogle Scholar
  77. Campbell ME, Spielberg SP, Kalow W (1987b) A urinary metabolic ratio that reflects systemic caffeine clearance. Clin Pharmacol Ther 42(2):157–165PubMedCrossRefGoogle Scholar
  78. Caraco Y, Zylber-Katz E, Berry EM, Levy M (1995) Caffeine pharmacokinetics in obesity and following significant weight reduction. Int J Obes 19(4):234–239Google Scholar
  79. Carrillo JA, Christensen M, Ramos SI, Alm C, Dahl ML, Benitez J, Bertilsson L (2000) Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine. Ther Drug Monit 22(4):409–417PubMedCrossRefGoogle Scholar
  80. Chen Y, Tu JH, He YJ, Zhang W, Wang G, Tan ZR, Zhou G, Fan L, Zhou HH (2009a) Effect of sodium tanshinone II A sulfonate on the activity of CYP1A2 in healthy volunteers. Xenobiotica 39(7):508–513PubMedCrossRefGoogle Scholar
  81. Chen Y, Xiao P, Ou-Yang DS, Fan L, Guo D, Wang YN, Han Y, Tu JH, Zhou G, Huang YF, Zhou HH (2009b) Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6. N-Acetyltransferase and xanthine oxidase activity in healthy volunteers. Clin Exp Pharmacol Physiol 36(8):828–833PubMedCrossRefGoogle Scholar
  82. Cheng WS, Murphy TL, Smith MT, Cooksley WG, Halliday JW, Powell LW (1990) Dose-dependent pharmacokinetics of caffeine in humans: relevance as a test of quantitative liver function. Clin Pharmacol Ther 47(4):516–524PubMedCrossRefGoogle Scholar
  83. Christensen M, Andersson K, Dalén P, Mirghani RA, Muirhead GJ, Nordmark A, Tybring G, Wahlberg A, Yaşar U, Bertilsson L (2003) The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Clin Pharmacol Ther 73(6):517–528PubMedCrossRefGoogle Scholar
  84. Chung WG, Kang JH, Park CS, Cho MH, Cha YN (2000) Effect of age and smoking on in vivo CYP1A2, flavin-containing monooxygenase, and xanthine oxidase activities in Koreans: determination by caffeine metabolism. Clin Pharmacol Ther 67(3):258–266PubMedCrossRefGoogle Scholar
  85. Chvasta TE, Cooke AR (1971) Emptying and absorption of caffeine from the human stomach. Gastroenterology 61(6):838–843PubMedGoogle Scholar
  86. Collomp K, Anselme F, Audran M, Gay JP, Chanal JL, Prefaut C (1991) Effects of moderate exercise on the pharmacokinetics of caffeine. Eur J Clin Pharmacol 40(3):279–282PubMedCrossRefGoogle Scholar
  87. Conner DP, Millora E, Zamani K, Nix D, Almirez RG, Rhyne-Kirsch P, Peck CC (1991) Transcutaneous chemical collection of caffeine in normal subjects: relationship to area under the plasma concentration-time curve and sweat production. J Invest Dermatol 96:186–190PubMedCrossRefGoogle Scholar
  88. Cooling DS (1993) Theophylline toxicity. J Emerg Med 11(4):415–425PubMedCrossRefGoogle Scholar
  89. Cornish HH, Christman AA (1957) A study of the metabolism of theobromine, theophylline, and caffeine in man. J Biol Chem 228(1):315–323PubMedGoogle Scholar
  90. Crowley JJ, Cusack BJ, Jue SG, Koup JR, Park BK, Vestal RE (1988) Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men. J Pharmacol Exp Ther 245(2):513–523PubMedGoogle Scholar
  91. Cysneiros RM, Farkas D, Harmatz JS, von Moltke LL, Greenblatt DJ (2007) Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine. Clin Pharmacol Ther 82(1):54–62PubMedCrossRefGoogle Scholar
  92. Danielson TJ, Golsteyn LR (1996) Systemic clearance and demethylation of caffeine in sheep and cattle. Drug Metab Dispos 24(10):1058–1061PubMedGoogle Scholar
  93. Darwish M, Kirby M, Robertson P Jr, Hellriegel ET (2008) Interaction profile of armodafinil with medications metabolized by P enzymes 1A2, 3A4 and 2C19 in healthy subjects. Clin Pharmacokinet 47(1):61–74PubMedCrossRefGoogle Scholar
  94. DeGraves FJ, Ruffin DC, Duran SH, Spano JS, Whatley EM, Schumacher J, Riddell MG (1995) Pharmacokinetics of caffeine in lactating dairy cows. Am J Vet Res 56(5):619–622PubMedGoogle Scholar
  95. Delahunty T, Schoendorfer D (1998) Caffeine demethylation monitoring using a transdermal sweat patch. J Anal Toxicol 22(7):596–600PubMedGoogle Scholar
  96. Denaro CP, Brown CR, Wilson M, Jacob P, Benowitz NL (1990) Dose-dependency of caffeine metabolism with repeated dosing. Clin Pharmacol Ther 48(3):277–285PubMedCrossRefGoogle Scholar
  97. Derby KS, Cuthrell K, Caberto C, Carmella SG, Franke AA, Hecht SS, Murphy SE, Le Marchand L (2008) Nicotine metabolism in three ethnic/racial groups with different risks of lung cancer. Cancer Epidemiol Biomarkers Prev 17(12):3526–3535PubMedCrossRefGoogle Scholar
  98. Derkenne S, Curran CP, Shertzer HG, Dalton TP, Dragin N, Nebert DW (2005) Theophylline pharmacokinetics: comparison of Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice, humanized hCYP1A1_1A2 knock-in mice lacking either the mouse Cyp1a1 or Cyp1a2 gene, and Cyp1(+/+) wild-type mice. Pharmacogenet Genomics 15(7):503–511PubMedCrossRefGoogle Scholar
  99. Desmond PV, Patwardhan RV, Johnson RF, Schenker S (1980) Impaired elimination of caffeine in cirrhosis. Dig Dis Sci 25(3):193–197PubMedCrossRefGoogle Scholar
  100. Devoe LD, Murray C, Youssif A, Arnaud M (1993) Maternal caffeine consumption and fetal behavior in normal third-trimester pregnancy. Am J Obstet Gynecol 168(4):1105–1111 (discussion 1111–1112)Google Scholar
  101. Djordjevic N, Ghotbi R, Bertilsson L, Jankovic S, Aklillu E (2008) Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol 64(4):381–385PubMedCrossRefGoogle Scholar
  102. Dorrbecker SH, Ferraina RA, Dorrbecker BR, Kramer PA (1987) Caffeine and paraxanthine pharmacokinetics in the rabbit: concentration and product inhibition effects. J Pharmacokinet Biopharm 15(2):117–132PubMedCrossRefGoogle Scholar
  103. Dorrbecker SH, Kramer PA, Dorrbecker BR, Raye JR (1988a) Caffeine disposition in the pregnant rabbit. II. Fetal distribution of caffeine and paraxanthine during chronic maternal caffeine administration. Dev Pharmacol Ther 11(2):118–124PubMedGoogle Scholar
  104. Dothey CI, Tserng KY, Kaw S, King KC (1989) Maturational changes of theophylline pharmacokinetics in preterm infants. Clin Pharmacol Ther 45(5):461–468PubMedCrossRefGoogle Scholar
  105. Doude van Troostwijk LJ, Koopmans RP, Vermeulen HD, Guchelaar HJ (2003a) CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients. Eur J Pharm Sci 20(4–5):451–457PubMedCrossRefGoogle Scholar
  106. Doude van Troostwijk LJ, Koopmans RP, Guchelaar HJ (2003b) Two novel methods for the determination of CYP1A2 activity using the paraxanthine/caffeine ratio. Fundam Clin Pharmacol 17(3):355–362PubMedCrossRefGoogle Scholar
  107. Driscoll MS, Ludden TM, Casto DT, Littlefield LC (1989) Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models. J Pharmacokinet Biopharm 17(2):141–168PubMedCrossRefGoogle Scholar
  108. Drouillard DD, Vesell ES, Dvorchik BH (1978) Studies on theobromine disposition in normal subjects. Alterations induced by dietary abstention from or exposure to methylxanthines. Clin Pharmacol Ther 23(3):296–302PubMedGoogle Scholar
  109. du Preez MJ, Botha JH, McFadyen ML, Holford NH (1999) The pharmacokinetics of theophylline in premature neonates during the first few days after birth. Ther Drug Monit 21(6):598–603PubMedCrossRefGoogle Scholar
  110. Ellis EF, Koysooko R, Levy G (1976) Pharmacokinetics of theophylline in children with asthma. Pediatrics 58(4):542–547PubMedGoogle Scholar
  111. Faber MS, Fuhr U (2004) Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther 76(2):178–184PubMedCrossRefGoogle Scholar
  112. Fleetham JA, Bird CE, Nakatsu K, Wigle RD, Munt PW (1981) Dose-dependency of theophylline clearance and protein binding. Thorax 36(5):382–386PubMedCrossRefGoogle Scholar
  113. Fontana RJ, deVries TM, Woolf TF, Knapp MJ, Brown AS, Kaminsky LS, Tang BK, Foster NL, Brown RR, Watkins PB (1998) Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer’s disease. Br J Clin Pharmacol 46(3):221–228PubMedCrossRefGoogle Scholar
  114. Fuhr U, Anders EM, Mahr G, Sörgel F, Staib AH (1992) Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro. Antimicrob Agents Chemother 36(5):942–948PubMedCrossRefGoogle Scholar
  115. Fuhr U, Klittich K, Staib AH (1993) Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol 35(4):431–436PubMedCrossRefGoogle Scholar
  116. Fuhr U, Maier A, Keller A, Steinijans VW, Sauter R, Staib AH (1995) Lacking effect of grapefruit juice on theophylline pharmacokinetics. Int J Clin Pharmacol Ther 33(6):311–314PubMedGoogle Scholar
  117. Fuhr U, Jetter A, Kirchheiner J (2007) Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther 81(2):270–83PubMedCrossRefGoogle Scholar
  118. Gal P, Jusko WJ, Yurchak AM, Franklin BA (1978) Theophylline disposition in obesity. Clin Pharmacol Ther 23(4):438–444PubMedGoogle Scholar
  119. Gardner MJ, Jusko WJ (1982) Effect of age and sex on theophylline clearance in young subjects. Pediatr Pharmacol 2(2):157–169Google Scholar
  120. Gardner MJ, Tornatore KM, Jusko WJ, Kanarkowski R (1983) Effects of tobacco smoking and oral contraceptive use on theophylline disposition. Br J Clin Pharmacol 16(3):271–280PubMedCrossRefGoogle Scholar
  121. Gardner MJ, Schatz M, Cousins L, Zeiger R, Middleton E, Jusko WJ (1987) Longitudinal effects of pregnancy on the pharmacokinetics of theophylline. Eur J Clin Pharmacol 32(3):289–295PubMedCrossRefGoogle Scholar
  122. Gates S, Miners JO (1999) Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism. Br J Clin Pharmacol 47(3):299–305PubMedCrossRefGoogle Scholar
  123. George J, Murphy T, Roberts R, Cooksley WG, Halliday JW, Powell LW (1986) Influence of alcohol and caffeine consumption on caffeine elimination. Clin Exp Pharmacol Physiol 13(10):731–736PubMedCrossRefGoogle Scholar
  124. Ghotbi R, Christensen M, Roh HK, Ingelman-Sundberg M, Aklillu E, Bertilsson L (2007) Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol 63(6):537–546PubMedCrossRefGoogle Scholar
  125. Gilbert SG, Stavric B, Klassen RD, Rice DC (1985) The fate of chronically consumed caffeine in the monkey (Macaca fascicularis). Fundam Appl Toxicol 5(3):578–587PubMedCrossRefGoogle Scholar
  126. Gorodischer R, Zmora E, Ben-Zvi Z, Warszawski D, Yaari A, Sofer S, Arnaud MJ (1986a) Urinary metabolites of caffeine in the premature infant. Eur J Clin Pharmacol 31(4):497–499PubMedCrossRefGoogle Scholar
  127. Gorodischer R, Yaari A, Margalith M, Warszawski D, Ben-Zvi Z (1986b) Changes in theophylline metabolism during postnatal development in rat liver slices. Biochem Pharmacol 35(18):3077–3081PubMedCrossRefGoogle Scholar
  128. Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ (2004) Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther 76(6):598–606PubMedCrossRefGoogle Scholar
  129. Granfors MT, Backman JT, Laitila J, Neuvonen PJ (2005) Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clin Pharmacol Ther 78(4):400–411PubMedCrossRefGoogle Scholar
  130. Grant DM, Tang BK, Kalow W (1983) Polymorphic N-acetylation of a caffeine metabolite. Clin Pharmacol Ther 33(3):355–359PubMedCrossRefGoogle Scholar
  131. Grant DM, Tang BK, Kalow W (1984) A simple test for acetylation phenotype using caffeine. Br J Clin Pharmacol 17(4):459–464PubMedCrossRefGoogle Scholar
  132. Grant DM, Tang BK, Campbell ME, Kalow W (1986) Effect of allopurinol on caffeine disposition in man. Br J Clin Pharmacol 21(4):454–458PubMedCrossRefGoogle Scholar
  133. Groen K, Horan MA, Roberts NA, Gulati RS, Miljkovic B, Jansen EJ, Paramsothy V, Breimer DD, van Bezooijen CF (1993) The relationship between phenazone (antipyrine) metabolite formation and theophylline metabolism in healthy and frail elderly women. Clin Pharmacokinet 25(2):136–144PubMedCrossRefGoogle Scholar
  134. Grosso LM, Bracken MB (2005) Caffeine metabolism, genetics, and perinatal outcomes: a review of exposure assessment considerations during pregnancy. Ann Epidemiol 15(6):460–466PubMedCrossRefGoogle Scholar
  135. Grosso LM, Triche E, Benowitz NL, Bracken MB (2008) Prenatal caffeine assessment: fetal and maternal biomarkers or self-reported intake? Ann Epidemiol 18(3):172–178PubMedCrossRefGoogle Scholar
  136. Grygiel JJ, Birkett DJ (1980) Effect of age on patterns of theophylline metabolism. Clin Pharmacol Ther 28(4):456–462PubMedCrossRefGoogle Scholar
  137. Grygiel JJ, Birkett DJ (1981) Cigarette smoking and theophylline clearance and metabolism. Clin Pharmacol Ther 30(4):491–496PubMedCrossRefGoogle Scholar
  138. Gu L, Gonzalez FJ, Kalow W, Tang BK (1992) Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 2(2):73–77PubMedCrossRefGoogle Scholar
  139. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY (2002) Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 72(3):276–287PubMedCrossRefGoogle Scholar
  140. Ha HR, Chen J, Freiburghaus AU, Follath F (1995) Metabolism of theophylline by cDNA-expressed human s P. Br J Clin Pharmacol 39(3):321–326PubMedCrossRefGoogle Scholar
  141. Ha HR, Chen J, Krahenbuhl S, Follath F (1996) Biotransformation of caffeine by cDNA-expressed human s P. Eur J Clin Pharmacol 49(4):309–315PubMedCrossRefGoogle Scholar
  142. Haller CA, Jacob P 3rd, Benowitz NL (2002) Pharmacology of ephedra alkaloids and caffeine after single-dose dietary supplement use. Clin Pharmacol Ther 71(6):421–432PubMedCrossRefGoogle Scholar
  143. Hamon-Vilcot B, Simon T, Becquemont L, Poirier JM, Piette F, Jaillon P (2004) Effects of malnutrition on cytochrome P450 1A2 activity in elderly patients. Therapie 59(2):247–251PubMedCrossRefGoogle Scholar
  144. Hashiguchi M, Fujimura A, Ohashi K, Ebihara A (1992) Diurnal effect on caffeine clearance. J Clin Pharmacol 32(2):184–187PubMedGoogle Scholar
  145. Hendeles L, Weinberger M, Bighley L (1977) Absolute bioavailability of oral theophylline. Am J Hosp Pharm 34(5):525–527PubMedGoogle Scholar
  146. Hendeles L, Massanari MJ, Weinberger M (1986) Theophylline. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied pharmacokinetics, 2nd edn. Applied Therapeutics, San Francisco, pp 1105–1188Google Scholar
  147. Holstege A, Staiger M, Haag K, Gerok W (1989) Correlation of caffeine elimination and Child’s classification in liver cirrhosis. Klin Wochenschr 67(1):6–15PubMedCrossRefGoogle Scholar
  148. Igarashi T, Iwakawa S (2009) Effect of gender on theophylline clearance in the asthmatic acute phase in Japanese pediatric patients. Biol Pharm Bull 32(2):304–307PubMedCrossRefGoogle Scholar
  149. Ingvast-Larsson C, Appelgren LE, Nyman G (1992) Distribution studies of theophylline: microdialysis in rat and horse and whole body autoradiography in rat. J Vet Pharmacol Ther 15(4):386–394PubMedCrossRefGoogle Scholar
  150. Jackson SH, Johnston A, Woollard R, Turner P (1989) The relationship between theophylline clearance and age in adult life. Eur J Clin Pharmacol 36(1):29–34PubMedCrossRefGoogle Scholar
  151. Jarboe CH, Hurst HE, Rodgers GC, Metaxas JM (1986) Toxicokinetics of caffeine elimination in an infant. Clin Toxicol 24(5):415–428CrossRefGoogle Scholar
  152. Jennings TS, Nafziger AN, Davidson L, Bertino JS Jr (1993) Gender differences in hepatic induction and inhibition of theophylline pharmacokinetics and metabolism. J Lab Clin Med 122(2):208–216PubMedGoogle Scholar
  153. Jeppesen U, Loft S, Poulsen HE, Brøsen K (1996) A fluvoxamine-caffeine interaction study. Pharmacogenetics 6(3):213–222PubMedCrossRefGoogle Scholar
  154. Jodynis-Liebert J, Flieger J, Matuszewska A, Juszczyk J (2004) Serum metabolite/caffeine ratios as a test for liver function. J Clin Pharmacol 44(4):338–347PubMedCrossRefGoogle Scholar
  155. Jonkman JH, van der Boon WJ, Balant LP, Le Cotonnec JY (1985) Food reduces the rate but not the extent of the absorption of theophylline from an aqueous solution. Eur J Clin Pharmacol 28(2):225–227PubMedCrossRefGoogle Scholar
  156. Jonkman JH, Sollie FA, Sauter R, Steinijans VW (1991) The influence of caffeine on the steady-state pharmacokinetics of theophylline. Clin Pharmacol Ther 49(3):248–255PubMedCrossRefGoogle Scholar
  157. Jung D, Nanavaty M (1990) The effects of age and dietary protein restriction on the pharmacokinetics of theophylline in the rat. Pharmacol Toxicol 66(5):361–366PubMedCrossRefGoogle Scholar
  158. Jusko WJ (1979) Influence of cigarette smoking on drug metabolism in man. Drug Metab Rev 9(2):221–236PubMedCrossRefGoogle Scholar
  159. Jusko WJ, Gardner MJ, Mangione A, Schentag JJ, Koup JR, Vance JW (1979) Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci 68(11):1358–1366PubMedCrossRefGoogle Scholar
  160. Kadlubar FF, Butler TG, MA TCH, Massengill JP, Lang NP (1990) Determination of carcinogenic arylamine N-oxidation phenotype in humans by analysis of caffeine urinary metabolites. Prog Clin Biol Res 340B:107–114PubMedGoogle Scholar
  161. Kall MA, Clausen J (1995) Dietary effect on mixed function P4501A2 activity assayed by estimation of caffeine metabolism in man. Hum Exp Toxicol 14(10):801–807PubMedCrossRefGoogle Scholar
  162. Kalow W (1986) Ethnic differences in reactions to drugs and xenobiotics Caffeine and other drugs. Prog Clin Biol Res 214:331–341PubMedGoogle Scholar
  163. Kalow W, Tang BK (1991a) Use of caffeine metabolic ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 50(5 Pt 1):508–519PubMedCrossRefGoogle Scholar
  164. Kalow W, Tang BK (1991b) Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. Clin Pharmacol Ther 49(1):44–48PubMedCrossRefGoogle Scholar
  165. Kamei K, Matsuda M, Momose A (1975) New sulfur-containing metabolites of caffeine. Chem Pharm Bull 23(3):683–685CrossRefGoogle Scholar
  166. Kamimori GH, Somani SM, Knowlton RG, Perkins RM (1987) The effects of obesity and exercise on the pharmacokinetics of caffeine in lean and obese volunteers. Eur J Clin Pharmacol 31(5):595–600PubMedCrossRefGoogle Scholar
  167. Kamimori GH, Lugo SI, Penetar DM, Chamberlain AC, Brunhart GE, Brunhart AE, Eddington ND (1995) Dose-dependent caffeine pharmacokinetics during severe sleep deprivation in humans. Int J Clin Pharmacol Ther 33(3):182–186PubMedGoogle Scholar
  168. Kawai H, Kokubun S, Matsumoto T, Kojima J, Onodera K (2000) Pharmacokinetic study of theophylline in dogs after intravenous administration with and without ethylenediamine. Methods Find Exp Clin Pharmacol 22(3):179–184PubMedGoogle Scholar
  169. Kearns GL, Hill DE, Tumbelson ME (1986) Theophylline and caffeine disposition in the neonatal piglet. Dev Pharmacol Ther 9(6):389–401PubMedGoogle Scholar
  170. Kilbane AJ, Silbart LK, Manis M, Beitins IZ, Weber WW (1990) Human N-acetylation genotype determination with urinary caffeine metabolites. Clin Pharmacol Ther 47(4):470–477PubMedCrossRefGoogle Scholar
  171. Kim YC, Lee AK, Lee JH, Lee I, Lee DC, Kim SH, Kim SG, Lee MG (2005) Pharmacokinetics of theophylline in diabetes mellitus rats: induction of CYP1A2 and CYP2E1 on 1,3-dimethyluric acid formation. Eur J Pharm Sci 26(1):114–123PubMedCrossRefGoogle Scholar
  172. Kimmel CA, Kimmel GL, White CG, Grafton TF, Young JF, Nelson CJ (1984) Blood flow changes and conceptal development in pregnant rats in response to caffeine. Fundam Appl Toxicol 4(2 Pt 1):240–247PubMedCrossRefGoogle Scholar
  173. Kimura M, Yamazaki H, Fujieda M, Kiyotani K, Honda G, Saruwatari J, Nakagawa K, Ishizaki T, Kamataki T (2005) Cyp2a6 is a principal enzyme involved in hydroxylation of 1,7-dimethylxanthine, a main caffeine metabolite, in humans. Drug Metab Dispos 33(9):1361–1366PubMedCrossRefGoogle Scholar
  174. Kinzig-Schippers M, Fuhr U, Zaigler M, Dammeyer J, Rüsing G, Labedzki A, Bulitta J, Sörgel F (1999) Interaction of pefloxacin and enoxacin with the human cytochrome P450 enzyme CYP1A2. Clin Pharmacol Ther 65(3):262–274PubMedCrossRefGoogle Scholar
  175. Kokwaro GO, Szwandt IS, Glazier AP, Ward SA, Edwards G (1993) Metabolism of caffeine and theophylline in rats with malaria and endotoxin-induced fever. Xenobiotica 23(12):1391–1397PubMedCrossRefGoogle Scholar
  176. Kolski GB, Levy J, Anolik R (1987) The use of theophylline clearance in pediatric status asthmaticus. I. Interpatient and intrapatient theophylline clearance variability. Am J Dis Child 141(3):282–287PubMedGoogle Scholar
  177. Korrapati MR, Vestal RE, Loi CM (1995) Theophylline metabolism in healthy nonsmokers and in patients with insulin-dependent diabetes mellitus. Clin Pharmacol Ther 57(4):413–418PubMedCrossRefGoogle Scholar
  178. Kotake AN, Schoeller DA, Lambert GH, Baker AL, Schaffer DO, Josephs H (1982) The caffeine CO2 breath test: dose response and route of N-demethylation in smokers and nonsmokers. Clin Pharmacol Ther 32(2):261–269PubMedCrossRefGoogle Scholar
  179. Kraus DM, Fischer JH, Reitz SJ, Kecskes SA, Yeh TF, McCulloch KM, Tung EC, Cwik MJ (1993) Alterations in theophylline metabolism during the first year of life. Clin Pharmacol Ther 54(4):351–359PubMedCrossRefGoogle Scholar
  180. Kuh HJ, Shim CK (1994) Nonlinear renal excretion of theophylline and its metabolites, 1-methyluric acid and 1,3-dimethyluric acid, in rats. Arch Pharm Res 17(2):124–130PubMedCrossRefGoogle Scholar
  181. Labedzki A, Buters J, Jabrane W, Fuhr U (2002) Differences in caffeine and paraxanthine metabolism between human and murine CYP1A2. Biochem Pharmacol 63(12):2159–67PubMedCrossRefGoogle Scholar
  182. Landi MT, Sinha R, Lang NP, Kadlubar FF (1999) Human cytochrome P4501A2. IARC Sci Publ 148:173–195PubMedGoogle Scholar
  183. Lane JD, Steege JF, Rupp SL, Kuhn CM (1992) Menstrual cycle effects on caffeine elimination in the human female. Eur J Clin Pharmacol 43(5):543–546PubMedCrossRefGoogle Scholar
  184. Latini R, Bonati M, Castelli D, Garattini S (1978) Dose-dependent kinetics of caffeine in rats. Toxicol Lett 2(5):267–270CrossRefGoogle Scholar
  185. Latini R, Bonati M, Marzi E, Garattini S (1981) Urinary excretion of an uracilic metabolite from caffeine by rat, monkey and man. Toxicol Lett 7(3):267–272PubMedCrossRefGoogle Scholar
  186. Latini R, Bonati M, Gaspari F, Traina GL, Jiritano L, Bortolotti A, Borzelleca JF, Tarka SM, Arnaud MJ, Garattini S (1984) Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits. Toxicology 30(4):343–354PubMedCrossRefGoogle Scholar
  187. Lau CE, Ma F, Falk JL (1995) Oral and IP caffeine pharmacokinetics under a chronic food-limitation condition. Pharmacol Biochem Behav 50(2):245–252PubMedCrossRefGoogle Scholar
  188. Le Marchand L, Sivaraman L, Franke AA, Custer LJ, Wilkens LR, Lau AF, Cooney RV (1996) Predictors of N-acetyltransferase activity: should caffeine phenotyping and NAT2 genotyping be used interchangeably in epidemiological studies? Cancer Epidemiol Biomarkers Prev 5(6):449–455PubMedGoogle Scholar
  189. Lee TC, Charles BG, Steer PA, Flenady VJ, Grant TC (1996) Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea. Br J Clin Pharmacol 41(3):191–200PubMedCrossRefGoogle Scholar
  190. Lelo A, Birkett DJ, Robson RA, Miners JO (1986a) Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man. Br J Clin Pharmacol 22(2):177–182PubMedCrossRefGoogle Scholar
  191. Lelo A, Miners JO, Robson RA, Birkett DJ (1986b) Quantitative assessment of caffeine partial clearances in man. Br J Clin Pharmacol 22(2):183–186PubMedCrossRefGoogle Scholar
  192. Lelo A, Kjellen G, Birkett DJ, Miners JO (1989) Paraxanthine metabolism in humans: determination of metabolic partial clearances and effects of allopurinol and cimetidine. J Pharmacol Exp Ther 248(1):315–319PubMedGoogle Scholar
  193. Lelo A, Birkett DJ, Miners JO (1990) Mechanism of formation of 6-amino-5-(N-methylformylamino)-1-methyluracil and 3,7-dimethyluric acid from theobromine in the rat in vitro: involvement of P- and a cellular thiol. Xenobiotica 20(8):823–833PubMedCrossRefGoogle Scholar
  194. Lenz TL, Lenz NJ, Faulkner MA (2004) Potential interactions between exercise and drug therapy. Sports Med 34(5):293–306PubMedCrossRefGoogle Scholar
  195. Lesko LJ, Tabor KJ, Johnson BF (1981) Theophylline serum protein binding in obstructive airways disease. Clin Pharmacol Ther 29(6):776–781PubMedCrossRefGoogle Scholar
  196. Levy M, Granit L, Zylber-Katz E (1984) Chronopharmacokinetics of caffeine in healthy volunteers. Annu Rev Chronopharmacol 1:97–100Google Scholar
  197. Loi CM, Parker BM, Cusack BJ, Vestal RE (1997) Aging and drug interactions. III. Individual and combined effects of cimetidine and cimetidine and ciprofloxacin on theophylline metabolism in healthy male and female nonsmokers. J Pharmacol Exp Ther 280(2):627–637PubMedGoogle Scholar
  198. Lowry JA, Jarrett RV, Wasserman G, Pettett G, Kauffman RE (2001) Theophylline toxicokinetics in premature newborns. Arch Pediatr Adolesc Med 155(8):934–939PubMedGoogle Scholar
  199. Madyastha KM, Sridhar GR (1998) A novel pathway for the metabolism of caffeine by a mixed culture consortium. Biochem Biophys Res Commun 249(1):178–181PubMedCrossRefGoogle Scholar
  200. Matzke GR, Frye RF, Early JJ, Straka RJ, Carson SW (2000) Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity. Pharmacotherapy 20(2):182–190PubMedCrossRefGoogle Scholar
  201. McLean C, Graham TE (2002) Effects of exercise and thermal stress on caffeine pharmacokinetics in men and eumenorrheic women. J Appl Physiol 93(4):1471–1478PubMedGoogle Scholar
  202. McManus ME, Miners JO, Gregor D, Stupans I, Birkett DJ (1988) Theophylline metabolism by human, rabbit and rat liver microsomes and by purified forms of cytochrome P450. J Pharm Pharmacol 40(6):388–391PubMedCrossRefGoogle Scholar
  203. McNamara PJ, Burgio D, Yoo SD (1992) Pharmacokinetics of caffeine and its demethylated metabolites in lactating adult rabbits and neonatal offspring. Predictions of breast milk to serum concentration ratios. Drug Metab Dispos 20(2):302–308PubMedGoogle Scholar
  204. Miller GE, Radulovic LL, DeWit RH, Brabec MJ, Tarka SM, Cornish HH (1984) Comparative theobromine metabolism in five mammalian species. Drug Metab Dispos 12(2):154–160PubMedGoogle Scholar
  205. Miners JO, Attwood J, Birkett DJ (1982) Theobromine metabolism in man. Drug Metab Dispos 10(6):672–675PubMedGoogle Scholar
  206. Miners JO, Attwood J, Wing LM, Birkett DJ (1985) Influence of cimetidine, sulfinpyrazone, and cigarette smoking on theobromine metabolism in man. Drug Metab Dispos 13(5):598–601PubMedGoogle Scholar
  207. Monks TJ, Caldwell J, Smith RL (1979) Influence of methylxanthine-containing foods on theophylline metabolism and kinetics. Clin Pharmacol Ther 26(4):513–524PubMedGoogle Scholar
  208. Monks TJ, Lawrie CA, Caldwell J (1981) The effect of increased caffeine intake on the metabolism and pharmacokinetics of theophylline in man. Biopharm Drug Dispos 2(1):31–37PubMedCrossRefGoogle Scholar
  209. Moore ES, Faix RG, Banagale RC, Grasela TH (1989) The population pharmacokinetics of theophylline in neonates and young infants. J Pharmacokinet Biopharm 17(1):47–66PubMedCrossRefGoogle Scholar
  210. Morisot C, Simoens C, Trublin F, Lhermitte M, Gremillet C, Robert MH, Lequin P (1990) Efficacité de la caffeine transcutanée dans le traitement des apnées du prématuré. Arch Fr Pediatr 47(3):221–224PubMedGoogle Scholar
  211. Mose T, Kjaerstad MB, Mathiesen L, Nielsen JB, Edelfors S, Knudsen LE (2008) Placental passage of benzoic acid, caffeine, and glyphosate in an ex vivo human perfusion system. J Toxicol Environ Health A 71(15):984–991PubMedCrossRefGoogle Scholar
  212. Mumford GK, Benowitz NL, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR (1996) Absorption rate of methylxanthines following capsules, cola and chocolate. Eur J Clin Pharmacol 51(3–4):319–325PubMedCrossRefGoogle Scholar
  213. Murphy TL, McIvor C, Yap A, Cooksley WG, Halliday JW, Powell LW (1988) The effect of smoking on caffeine elimination: implications for its use as a semiquantitative test of liver function. Clin Exp Pharmacol Physiol 15(1):9–13PubMedCrossRefGoogle Scholar
  214. Murray RD, Breech L, Ailabouni A, Zingerelli J, Nahata MC (1993) Absorption of theophylline from the small and large intestine of the neonatal piglet. Eur J Drug Metab Pharmacokinet 18(4):375–379PubMedCrossRefGoogle Scholar
  215. Muscat JE, Pittman B, Kleinman W, Lazarus P, Stellman SD, Richie JP Jr (2008) Comparison of CYP1A2 and NAT2 phenotypes between black and white smokers. Biochem Pharmacol 76(7):929–937PubMedCrossRefGoogle Scholar
  216. Nagel RA, Dirix LY, Hayllar KM, Preisig R, Tredger JM, Williams R (1990) Use of quantitative liver function tests-caffeine clearance and galactose elimination capacity-after orthotopic liver transplantation. J Hepatol 10(2):149–157PubMedCrossRefGoogle Scholar
  217. Nakazawa K, Tanaka H, Arima M (1985) The effect of caffeine ingestion on pharmacokinetics of caffeine and its metabolites after a single administration in pregnant rats. J Pharmacobiodyn 8(3):151–160PubMedCrossRefGoogle Scholar
  218. Nam BH, Sohn DH, Ko G, Kim JB (1997) Effect of hepatic cirrhosis on the pharmacokinetics of theophylline in rats. Arch Pharm Res 20(4):318–323PubMedCrossRefGoogle Scholar
  219. Newton R, Broughton LJ, Lind MJ, Morrisson PJ, Rogers HJ, Bradbrook ID (1981) Plasma and salivary pharmacokinetics of caffeine in man. Eur J Clin Pharmacol 21(1):45–52PubMedCrossRefGoogle Scholar
  220. Obase Y, Shimoda T, Kawano T, Saeki S, Tomari S, Matsuse H, Kinoshita M, Kohno S (2003) Polymorphisms in the CYP1A2 gene and metabolism in patients with asthma. Clin Pharmacol Ther 73:468–474PubMedCrossRefGoogle Scholar
  221. Ogilvie RI (1978) Clinical pharmacokinetics of theophylline. Clin Pharmacokinet 3(4):267–293PubMedCrossRefGoogle Scholar
  222. Oliveto AH, Hughes JR, Terry SY, Bickel WK, Higgins ST, Pepper SL, Fenwick JW (1991) Effects of caffeine on tobacco withdrawal. Clin Pharmacol Ther 50(2):157–164PubMedCrossRefGoogle Scholar
  223. Omarini D, Barzago MM, Bortolotti A, Aramayona J, Bonati M (1991) Placental transfer of theophylline during in situ perfusion in the rabbit. J Pharmacol Methods 25(4):263–273PubMedCrossRefGoogle Scholar
  224. Ou-Yang DS, Huang SL, Wang W, Xie HG, Xu ZH, Shu Y, Zhou HH (2000) Phenotypic polymorphism and gender-related differences of CYP1A2 activity in a Chinese population. Br J Clin Pharmacol 49(2):145–151PubMedCrossRefGoogle Scholar
  225. Pan WJ, Goldwater DR, Zhang Y, Pilmer BL, Hunt RH (2000) Lack of a pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline. Aliment Pharmacol Ther 14(3):345–352PubMedCrossRefGoogle Scholar
  226. Park EJ, Ko G, Kim J, Sohn DH (1999) Biotransformation of theophylline in cirrhotic rats induced by biliary obstruction. Arch Pharm Res 22(1):60–67PubMedCrossRefGoogle Scholar
  227. Park GJ, Katelaris PH, Jones DB, Seow F, Le Couteur DG, Ngu MC (2003) Validity of the 13C-caffeine breath test as a noninvasive, quantitative test of liver function. Hepatology 38(5):1227–1236PubMedCrossRefGoogle Scholar
  228. Parra P, Limon A, Ferre S, Guix T, Jane F (1991) High-performance liquid chromatographic separation of caffeine, theophylline, theobromine and paraxanthine in rat brain and serum. J Chromatogr 570(1):185–190PubMedCrossRefGoogle Scholar
  229. Parsons W, Neims A (1978) Effect of smoking on caffeine clearance. Clin Pharmacol Ther 24(1):40–45PubMedGoogle Scholar
  230. Patwardhan R, Desmond P, Johnson R, Schenker S (1980) Impaired elimination of caffeine by oral contraceptive steroid. J Lab Clin Med 95(4):603–608PubMedGoogle Scholar
  231. Perry DF, Walson PD, Blanchard J (1984) Effect of pH on theophylline transfer across the everted rat jejunum. J Pharm Sci 73(3):320–325PubMedCrossRefGoogle Scholar
  232. Pons G, Blais J-C, Rey E, Plissonnier M, Richard M-O, Carrier O, D'Athis P, Moran Badoual J, Olive G (1988) Maturation of caffeine N-demethylation in infancy: a study using the 13CO2 breath test. Pediatr Res 23(6):632–636PubMedCrossRefGoogle Scholar
  233. Powell JR, Thiercelin JF, Vozeh S, Sansom L, Riegelman S (1977) The influence of cigarette smoking and sex on theophylline disposition. Am Rev Respir Dis 116(1):17–23PubMedGoogle Scholar
  234. Rasmussen BB, Brix TH, Kyvik KO, Brøsen K (2002) The differences in the 3-demethylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Pharmacogenetics 12:473–478PubMedCrossRefGoogle Scholar
  235. Renner E, Wietholtz H, Huguenin P, Arnaud MJ, Preisig R (1984) Caffeine: a model compound for measuring liver function. Hepatology 4(1):38–46PubMedCrossRefGoogle Scholar
  236. Resman BH, Blumenthal P, Jusko WJ (1977) Breast milk distribution of theobromine from chocolate. J Pediatr 91(3):477–480PubMedCrossRefGoogle Scholar
  237. Rietveld EC, Broekman MM, Houben JJ, Eskes TK, van Rossum JM (1984) Rapid onset of an increase in caffeine residence time in young women due to oral contraceptive steroids. Eur J Clin Pharmacol 26(3):371–373PubMedCrossRefGoogle Scholar
  238. Robson RA, Miners JO, Matthews AP, Stupans I, Meller D, McManus ME, Birkett DJ (1988) Characterisation of theophylline metabolism by human liver microsomes. Inhibition and immunochemical studies. Biochem Pharmacol 37(9):1651–1659PubMedCrossRefGoogle Scholar
  239. Robson RA (1992) The effects of quinolones on xanthine pharmacokinetics. Am J Med 92(4A):22S–25SGoogle Scholar
  240. Rodopoulos N, Norman A (1996) Assessment of dimethylxanthine formation from caffeine in healthy adults: comparison between plasma and saliva concentrations and urinary excretion of metabolites. Scand J Clin Lab Invest 56(3):259–268PubMedCrossRefGoogle Scholar
  241. Rodopoulos N, Höjvall L, Norman A (1996) Elimination of theobromine metabolites in healthy adults. Scand J Clin Lab Invest 56(4):373–383PubMedCrossRefGoogle Scholar
  242. Rodopoulos N, Norman A (1997) Elimination of theophylline metabolites in healthy adults. Scand J Clin Lab Invest 57(3):233–240PubMedCrossRefGoogle Scholar
  243. Rosal R, Rodríguez A, Perdigón-Melón JA, Petre A, García-Calvo E, Gómez MJ, Agüera A, Fernández-Alba AR (2010) Occurrence of emerging pollutants in urban wastewater and their removal through biological treatment followed by ozonation. Water Res 44(2):578–588PubMedCrossRefGoogle Scholar
  244. Rost KL, Roots I (1994) Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios: coincidence with plasma clearance and breath test. Clin Pharmacol Ther 55(4):402–411PubMedCrossRefGoogle Scholar
  245. Ryu JY, Song IS, Sunwoo YE, Shon JH, Liu KH, Cha IJ, Shin JG (2007) Development of the “Inje cocktail” for high-throughput evaluation of five human cytochrome P450 isoforms in vivo. Clin Pharmacol Ther 82(5):531–540PubMedCrossRefGoogle Scholar
  246. Sachse KT, Jackson EK, Wisniewski SR, Gillespie DG, Puccio AM, Clark RS, Dixon CE, Kochanek PM (2008) Increases in cerebrospinal fluid caffeine concentration are associated with favorable outcome after severe traumatic brain injury in humans. J Cereb Blood Flow Metab 28(2):395–401PubMedCrossRefGoogle Scholar
  247. Salomon G (1883) Über Paraxanthine und Heteroxanthin. Ber Dtsch Chem Ges 18:3406–3410CrossRefGoogle Scholar
  248. Sarkar MA, Hunt C, Guzelian PS, Karnes HT (1992) Characterization of human liver cytochromes P-450 involved in theophylline metabolism. Drug Metab Dispos 20(1):31–37PubMedGoogle Scholar
  249. Sarkar MA, Jackson BJ (1994) Theophylline N-demethylations as probes for P4501A1 and P4501A2. Drug Metab Dispos 22(6):827–834PubMedGoogle Scholar
  250. Saruwatari J, Nakagawa K, Shindo J, Tajiri T, Fujieda M, Yamazaki H, Kamataki T, Ishizaki T (2002) A population phenotyping study of three drug-metabolizing enzymes in Kyushu, Japan, with use of the caffeine test. Clin Pharmacol Ther 72(2):200–208PubMedCrossRefGoogle Scholar
  251. Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K (1993) Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects. Eur J Clin Pharmacol 44(3):295–298PubMedCrossRefGoogle Scholar
  252. Sato S, Nakajima M, Honda A, Konishi T, Miyazaki H (2007) Pharmacokinetics of theophylline in Guinea pig tears. Drug Metab Pharmacokinet 22(3):169–177PubMedCrossRefGoogle Scholar
  253. Schaad HJ, Renner EL, Wietholtz H, Arnaud MJ, Preisig R (1995) Caffeine demethylation measured by breath analysis in experimental liver injury in the rat. J Hepatol 22(1):82–87PubMedCrossRefGoogle Scholar
  254. Schlaeffer F, Engelberg I, Kaplanski J, Danon A (1984) Effect of exercise and environmental heat on theophylline kinetics. Respiration 45(4):438–442PubMedCrossRefGoogle Scholar
  255. Schmider J, Brockmöller J, Arold G, Bauer S, Roots I (1999) Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics 9(6):725–734PubMedCrossRefGoogle Scholar
  256. Schrenk D (1998) Impact of dioxin-type induction of drug-metabolizing enzymes on the metabolism of endo- and xenobiotics. Biochem Pharmacol 5(8):1155–1162Google Scholar
  257. Scott NR, Chakraborty J, Marks V (1984) Determination of caffeine, theophylline and theobromine in serum and saliva using high-performance liquid chromatography. Ann Clin Biochem 21(Pt 2):120–124PubMedGoogle Scholar
  258. Scott NR, Chakraborty J, Marks V (1986) Urinary metabolites of caffeine in pregnant women. Br J Clin Pharmacol 22(4):475–478PubMedCrossRefGoogle Scholar
  259. Scott NR, Stambuk D, Chakraborty J, Marks V, Morgan MY (1988) Caffeine clearance and biotransformation in patients with chronic liver disease. Clin Sci 74(4):377–384PubMedGoogle Scholar
  260. Scott NR, Stambuk D, Chakraborty J, Marks V, Morgan MY (1989) The pharmacokinetics of caffeine and its dimethylxanthine metabolites in patients with chronic liver disease. Br J Clin Pharmacol 27(2):205–213PubMedCrossRefGoogle Scholar
  261. Shaw LM, Fields L, Mayock R (1982) Factors influencing theophylline serum protein binding. Clin Pharmacol Ther 32(4):490–496PubMedCrossRefGoogle Scholar
  262. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P- 450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–423PubMedGoogle Scholar
  263. Shively CA, Tarka SM Jr (1983) Theobromine metabolism and pharmacokinetics in pregnant and nonpregnant Sprague-Dawley rats. Toxicol Appl Pharmacol 67(3):376–382PubMedCrossRefGoogle Scholar
  264. Shively CA, Tarka SM Jr (1984) Methylxanthine composition and consumption patterns of cocoa and chocolate products. In: Spiller GA (ed) The methylxanthine beverages in foods: chemistry, consumption, and health effects. Alan R Liss, New York, pp 149–178Google Scholar
  265. Shively CA, Tarka SM Jr, Arnaud MJ, Dvorchik BH, Passananti GT, Vesell ES (1985) High levels of methylxanthines in chocolate do not alter theobromine disposition. Clin Pharmacol Ther 37(4):415–424PubMedCrossRefGoogle Scholar
  266. Siegel IA, Ben-Aryeh H, Gozal D, Colin AA, Szargel R, Laufer D (1990) Comparison of unbound and total serum theophylline concentrations with those of stimulated and unstimulated saliva in asthmatic children. Ther Drug Monit 12(5):460–464PubMedCrossRefGoogle Scholar
  267. Simons FE, Rigatto H, Simons KJ (1981) Pharmacokinetics of theophylline in neonates. Semin Perinatol 5(4):337–345PubMedGoogle Scholar
  268. Sjöberg P, Olofsson IM, Lundqvist T (1992) Validation of different microdialysis methods for the determination of unbound steady-state concentrations of theophylline in blood and brain tissue. Pharm Res 9(12):1592–1598PubMedCrossRefGoogle Scholar
  269. Soyka LF, Neese AL, Main D, Main E (1981) Studies of caffeine and theophylline in the neonate. Semin Perinatol 5(4):332–336PubMedGoogle Scholar
  270. Sperber AD (1991) Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy. Drug Saf 6(6):460–462PubMedCrossRefGoogle Scholar
  271. Spigset O, Hägg S, Söderström E, Dahlqvist R (1999a) The paraxanthine:caffeine ratio in serum or in saliva as a measure of CYP1A2 activity: when should the sample be obtained? Pharmacogenetics 9(3):409–412PubMedCrossRefGoogle Scholar
  272. Spigset O, Hägg S, Söderström E, Dahlqvist R (1999b) Lack of correlation between fluvoxamine clearance and CYP1A2 activity as measured by systemic caffeine clearance. Eur J Clin Pharmacol 54(12):943–946PubMedCrossRefGoogle Scholar
  273. Ståhle L (1991) Drug distribution studies with microdialysis: I. Tissue dependent difference in recovery between caffeine and theophylline. Life Sci 49(24):1835–1842PubMedCrossRefGoogle Scholar
  274. Ståhle L, Segersvärd S, Ungerstedt U (1991) Drug distribution studies with microdialysis. II. Caffeine and theophylline in blood, brain and other tissues in rats. Life Sci 49(24):1843–1852PubMedCrossRefGoogle Scholar
  275. Statland BE, Demas TJ (1980) Serum caffeine half-lives. Healthy subjects vs. patients having alcoholic hepatic disease. Am J Clin Pathol 73(3):90–393Google Scholar
  276. Straka RJ, Burkhardt RT, Lang NP, Hadsall KZ, Tsai MY (2006) Discordance between N-acetyltransferase 2 phenotype and genotype in a population of Hmong subjects. J Clin Pharmacol 46(7):802–11PubMedCrossRefGoogle Scholar
  277. Streetman DS, Bleakley JF, Kim JS, Nafziger AN, Leeder JS, Gaedigk A, Gotschall R, Kearns GL, Bertino JS Jr (2000) Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the “Cooperstown cocktail”. Clin Pharmacol Ther 68(4):375–383PubMedCrossRefGoogle Scholar
  278. Takata K, Saruwatari J, Nakada N, Nakagawa M, Fukuda K, Tanaka F, Takenaka S, Mihara S (2006) Phenotype-genotype analysis of CYP1A2 in Japanese patients receiving oral theophylline therapy. Eur J Clin Pharmacol 62(1):23–28PubMedCrossRefGoogle Scholar
  279. Tanaka E, Ishikawa A, Yamamoto Y, Uchida E, Kobayashi S, Yasuhara H, Misawa S (1992a) Simplified approach for evaluation of hepatic drug-oxidizing capacity with a simultaneous measurement of caffeine and its primary demethylated metabolites in carbon tetrachloride-intoxicated rats. Xenobiotica 22(5):535–541PubMedCrossRefGoogle Scholar
  280. Tanaka E, Ishikawa A, Yamamoto Y, Osada A, Tsuji K, Fukao K, Misawa S, Iwasaki Y (1992b) A simple useful method for the determination of hepatic function in patients with liver cirrhosis using caffeine and its three major dimethylmetabolites. Int J Clin Pharmacol Ther Toxicol 30(9):336–341PubMedGoogle Scholar
  281. Tanaka E, Ishikawa A, Yamamoto Y, Osada A, Tsuji K, Fukao K, Iwasaki Y (1993) Comparison of hepatic drug-oxidizing activity after simultaneous administration of two probe drugs, caffeine and trimethadione, to human subjects. Pharmacol Toxicol 72(1):31–33PubMedCrossRefGoogle Scholar
  282. Tanaka E, Ishikawa A, Misawa S (1995) Changes in the metabolism of three model substrates catalysed by different P isozymes when administered as a cocktail to the carbon tetrachloride-intoxicated rat. Xenobiotica 25(10):1111–1118PubMedCrossRefGoogle Scholar
  283. Tang BK, Grant DM, Kalow W (1983) Isolation and identification of 5-acetylamino-6-formylamino-3-methyluracil as a major metabolite of caffeine in man. Drug Metab Dispos 11(3):218–220PubMedGoogle Scholar
  284. Tang BK, Zubovits T, Kalow W (1986) Determination of acetylated caffeine by high-performance exclusion chromatography. J Chromatogr 375(1):170–173Google Scholar
  285. Tang BK, Zhou Y, Kadar D, Kalow W (1994) Caffeine as a probe for CYP1A2 activity: potential influence of renal factors on urinary phenotypic trait measurements. Pharmacogenetics 4(3):117–224PubMedCrossRefGoogle Scholar
  286. Tang-Liu DD, Riegelman S (1981) Metabolism of theophylline to caffeine in adults. Res Commun Chem Pathol Pharmacol 34(3):371–380PubMedGoogle Scholar
  287. Tang-Liu DDS, Williams RL, Reigelman S (1983) Disposition of caffeine and its metabolites in man. J Pharmacol Exp Ther 224(1):180–185PubMedGoogle Scholar
  288. Tarka SM Jr (1982) The toxicology of cocoa and methylxanthines: a review of the literature. Crit Rev Toxicol 9(4):275–312PubMedCrossRefGoogle Scholar
  289. Tarka SM Jr, Arnaud MJ, Dvorchik BH, Vesell ES (1983) Theobromine kinetics and metabolic disposition. Clin Pharmacol Ther 34(4):546–555PubMedCrossRefGoogle Scholar
  290. Tassaneeyakul W, Birkett DJ, McManus ME, Tassaneeyakul W, Veronese ME, Andersson T, Tukey RH, Miners JO (1994) Caffeine metabolism by human hepatic cytochromes P450: contributions of 1A2, 2E1 and 3A isoforms. Biochem Pharmacol 47(10):1767–1776PubMedCrossRefGoogle Scholar
  291. Teichmann AT (1990) Influence of oral contraceptives on drug therapy. Am J Obstet Gynecol 163(6 Pt 2):2208–2213PubMedGoogle Scholar
  292. Teunissen MW, Brorens IO, Geerlings JM, Breimer DD (1985) Dose-dependent elimination of theophylline in rats. Xenobiotica 15(2):165–171PubMedCrossRefGoogle Scholar
  293. Tornatore KM, Kanarkowski R, McCarthy TL, Gardner MJ, Yurchak AM, Jusko WJ (1982) Effect of chronic oral contraceptive steroids on theophylline disposition. Eur J Clin Pharmacol 23(2):129–134PubMedCrossRefGoogle Scholar
  294. Trang JM, Blanchard J, Conrad KA, Harrison GG (1985) Relationship between total body clearance of caffeine and urine flow rate in elderly men. Biopharm Drug Dispos 6(1):51–56PubMedCrossRefGoogle Scholar
  295. Trnavská Z (1990) Theophylline protein binding. Arzneimittelforschung 40(2 Pt 1):166–169PubMedGoogle Scholar
  296. Tröger U, Meyer FP (1995) Influence of endogenous and exogenous effectors on the pharmacokinetics of theophylline focus on biotransformation. Clin Pharmacokinet 28(4):287–314PubMedCrossRefGoogle Scholar
  297. Tserng KY, Takieddine FN, King KC (1983) Developmental aspects of theophylline metabolism in premature infants. Clin Pharmacol Ther 33(4):522–528PubMedCrossRefGoogle Scholar
  298. Tsutsumi K, Kotegawa T, Matsuki S, Tanaka Y, Ishii Y, Kodama Y, Kuranari M, Miyakawa I, Nakano S (2001) The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans. Clin Pharmacol Ther 70(2):121–125PubMedCrossRefGoogle Scholar
  299. Tukker JJ, Meulendijk AJ (1991) Is a diurnal rhythm in bioavailability caused by a rhythm in intestinal absorption? Eur J Drug Metab Pharmacokinet Spec No 3:66–70Google Scholar
  300. Upton RA (1991) Pharmacokinetic interactions between theophylline and other medication (Part I). Clin Pharmacokinet 20(1):66–80PubMedCrossRefGoogle Scholar
  301. Vickroy TW, Chang SK, Chou CC (2008) Caffeine-induced hyperactivity in the horse: comparisons of drug and metabolite concentrations in blood and cerebrospinal fluid. J Vet Pharmacol Ther 31(2):156–166PubMedCrossRefGoogle Scholar
  302. Vistisen K, Loft S, Poulsen HE (1991) Cytochrome P450 IA2 activity in man measured by caffeine metabolism: effect of smoking, broccoli and exercise. Adv Exp Biol Biol 283:407–411CrossRefGoogle Scholar
  303. Vistisen K, Poulsen HE, Loft S (1992) Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Carcinogenesis 13(9):1561–1568PubMedCrossRefGoogle Scholar
  304. Walton K, Dorne JL, Renwick AG (2001) Uncertainty factors for chemical risk assessment: interspecies differences in the in vivo pharmacokinetics and metabolism of human CYP1A2 substrates. Food Chem Toxicol 39(7):667–680PubMedCrossRefGoogle Scholar
  305. Warszawski D, Gorodischer R, Moses SW, Bark H (1977) Caffeine pharmacokinetics in young and adult dogs. Biol Neonate 32(3–4):138–142PubMedGoogle Scholar
  306. Warszawski D, Ben-Zvi Z, Gorodischer R, Arnaud MJ, Bracco I (1982) Urinary metabolites of caffeine in young dogs. Drug Metab Dispos 10(4):424–428PubMedGoogle Scholar
  307. Weinberger M, Ginchansky E (1977) Dose-dependent kinetics of theophylline disposition in asthmatic children. J Pediatr 91(5):820–824PubMedCrossRefGoogle Scholar
  308. Wietholtz H, Voegelin M, Arnaud MJ, Bircher J, Preisig R (1981) Assessment of cytochrome P-448 dependent liver enzyme system by a caffeine breath test. Eur J Clin Pharmacol 21(1):53–59PubMedCrossRefGoogle Scholar
  309. Wijnands GJ, Cornel JH, Martea M, Vree TB (1990) The effect of multiple-dose oral lomefloxacin on theophylline metabolism in man. Chest 98(6):1440–1444PubMedCrossRefGoogle Scholar
  310. Wilkinson JM, Pollard I (1993) Accumulation of theophylline, theobromine and paraxanthine in the fetal rat brain following a single oral dose of caffeine. Brain Res Dev Brain Res 75(2):193–199PubMedCrossRefGoogle Scholar
  311. Wu C, Witter JD, Spongberg AL, Czajkowski KP (2009) Occurrence of selected pharmaceuticals in an agricultural landscape, western Lake Erie basin. Water Res 43(14):3407–416PubMedCrossRefGoogle Scholar
  312. Xu H, Rajesan R, Harper P, Kim RB, Lonnerdal B, Yang M, Uematsu S, Hutson J, Watson-MacDonell J, Ito S (2005) Induction of P 1A by cow milk-based formula: a comparative study between human milk and formula. Br J Pharmacol 146(2):296–305PubMedCrossRefGoogle Scholar
  313. Yang KH, Lee JH, Lee MG (2008) Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU. J Pharm Pharmacol 60(1):45–53PubMedCrossRefGoogle Scholar
  314. Yano I, Tanigawara Y, Yasuhara M, Mikawa H, Hori R (1993) Population pharmacokinetics of theophylline. I: Intravenous infusion to children in the acute episode of asthma. Biol Pharm Bull 16(1):59–62PubMedCrossRefGoogle Scholar
  315. Yesair DW, Branfman AR, Callahan MM (1984) Human disposition and some biochemical aspects of methylxanthines. Prog Clin Biol Res 158:215–233PubMedGoogle Scholar
  316. Zandvliet AS, Huitema AD, de Jonge ME, den Hoed R, Sparidans RW, Hendriks VM, van den Brink W, van Ree JM, Beijnen JH (2005) Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine. Basic Clin Pharmacol Toxicol 96(1):71–79PubMedCrossRefGoogle Scholar
  317. Zevin S, Benowitz NL (1999) Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 36(6):425–438PubMedCrossRefGoogle Scholar
  318. Zhang Z-Y, Kaminsky LS (1995) Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol 50(2):205–211PubMedCrossRefGoogle Scholar
  319. Zhu B, Ou-Yang DS, Chen XP, Huang SL, Tan ZR, He N, Zhou HH (2001) Assessment of cytochrome P450 activity by a five-drug cocktail approach. Clin Pharmacol Ther 70(5):455–461PubMedCrossRefGoogle Scholar
  320. Zysset T, Wietholtz H (1991) Pharmacokinetics of caffeine in patients with decompensated type I and type II diabetes mellitus. Eur J Clin Pharmacol 41(5):449–452PubMedCrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Nutrition and BiochemistryLa Tour-de-PeilzSwitzerland

Personalised recommendations