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Multiple Peaking Phenomena in Pharmacokinetic Disposition

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Abstract

multiple peaking in the blood fluid concentration-time curve is a phenomenon occasionally encountered in pharmacokinetics. When it occurs, it can create difficulties in the determination and interpretation of pharmacokinetic parameters. Multiple peaking can occur as a consequence of a number of different mechanisms. These include, in addition to others, factors related to the formulation, be it the drug chemical entity itself or other formulation-related factors such as the excipients incorporated into the product design. Another contributing factor that can work in concert with the formulation is the physiological makeup of the gastrointestinal tract itself. This includes the pH and components of bile such as bile salts and phospholipids, the secretion of which is regulated by hormonal and dietary factors. In some cases, biochemical differences in the regional areas of the gastrointestinal tract, such as regiospecificity in bile concentrations and/or transport proteins, could contribute to windows for absorption that result in multiple peaking of xenobiotics. One of the most common sources of multiple peaking is contributed by biliary secretion followed by intestinal reabsorption of a drug, a process for which the term ‘enterohepatic recycling’ has been coined. This cause of multiple peaking is associated with special consideration in the calculation and interpretation of the drug clearance and volume of distribution. In this review, each of these various causes of multiple peaking is discussed, with incorporation of relevant examples for illustrative purposes.

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References

  1. McClain DA, Hug Jr CC. Intravenous fentanyl kinetics. Clin Pharmacol Ther 1980 Jul; 28(1): 106–14

    Article  PubMed  CAS  Google Scholar 

  2. Bentley JB, Borel JD, Nenad Jr RE, et al. Age and fentanyl pharmacokinetics. Anesth Analg 1982 Dec; 61(12): 968–71

    Article  PubMed  CAS  Google Scholar 

  3. Hudson RJ, Thomson IR, Cannon JE, et al. Pharmacokinetics of fentanyl in patients undergoing abdominal aortic surgery. Anesthesiology 1986 Mar; 64(3): 334–8

    Article  PubMed  CAS  Google Scholar 

  4. Stoeckel H, Schuttler J, Magnussen H, et al. Plasma fentanyl concentrations and the occurrence of respiratory depression in volunteers. Br J Anaesth 1982 Oct; 54(10): 1087–95

    Article  PubMed  CAS  Google Scholar 

  5. Katz R, Kelly HW. Pharmacokinetics of continuous infusions of fentanyl in critically ill children. Crit Care Med 1993 Jul; 21(7): 995–1000

    Article  PubMed  CAS  Google Scholar 

  6. Bjorkman S, Wada DR, Stanski DR. Application of physiologic models to predict the influence of changes in body composition and blood flows on the pharmacokinetics of fentanyl and alfentanil in patients. Anesthesiology 1998 Mar; 88(3): 657–67

    Article  PubMed  CAS  Google Scholar 

  7. Hudson RJ, Thomson IR, Burgess PM, et al. Alfentanil pharmacokinetics in patients undergoing abdominal aortic surgery. Can J Anaesth 1991 Jan; 38(1): 61–7

    Article  PubMed  CAS  Google Scholar 

  8. Camu F, Gepts E, Rucquoi M, et al. Pharmacokinetics of alfentanil in man. Anesth Analg 1982 Aug; 61(8): 657–61

    Article  PubMed  CAS  Google Scholar 

  9. Bjorkman S, Stanski DR, Verotta D, et al. Comparative tissue concentration profiles of fentanyl and alfentanil in humans predicted from tissue/blood partition data obtained in rats. Anesthesiology 1990 May; 72(5): 865–73

    Article  PubMed  CAS  Google Scholar 

  10. Bjorkman S, Stanski DR, Harashima H, et al. Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model. J Pharmacokinet Biopharm 1993 Jun; 21(3): 255–79

    PubMed  CAS  Google Scholar 

  11. Bjorkman S, Wada DR, Stanski DR, et al. Comparative physiological pharmacokinetics of fentanyl and alfentanil in rats and humans based on parametric single-tissue models. J Pharmacokinet Biopharm 1994 Oct; 22(5): 381–410

    PubMed  CAS  Google Scholar 

  12. Estebe JP, Le Corre P, Levron JC, et al. Pilot study on the effect of tourniquet use on sufentanil pharmacokinetics. J Clin Anesth 2002 Dec; 14(8): 578–83

    Article  PubMed  CAS  Google Scholar 

  13. Kay NH, Uppington J, Sear JW, et al. Pharmacokinetics of propofol (’Diprivan’) as an induction agent. Postgrad Med J 1985; 61 Suppl. 3: 55–7

    PubMed  Google Scholar 

  14. Morgan DJ, Blackman GL, Paull JD, et al. Pharmacokinetics and plasma binding of thiopental: II. Studies at cesarean section. Anesthesiology 1981 Jun; 54(6): 474–80

    CAS  Google Scholar 

  15. Morgan DJ, Blackman GL, Paull JD, et al. Pharmacokinetics and plasma binding of thiopental: I. Studies in surgical patients. Anesthesiology 1981 Jun; 54(6): 468–73

    CAS  Google Scholar 

  16. Moore RG, McBride WG. The disposition kinetics of diazepam in pregnant women at parturition. Eur J Clin Pharmacol 1978 Jun 19; 13(4): 275–84

    Article  PubMed  CAS  Google Scholar 

  17. Lennernas H, Regardh CG. Evidence for an interaction between the beta-blocker pafenolol and bile salts in the intestinal lumen of the rat leading to dose-dependent oral absorption and double peaks in the plasma concentration-time profile. Pharm Res 1993 Jun; 10(6): 879–83

    Article  PubMed  CAS  Google Scholar 

  18. Lennernas H, Renberg L, Hoffmann KJ, et al. Presystemic elimination of the beta-blocker pafenolol in the rat after oral and intraperitoneal administration and identification of a main metabolite in both rats and humans. Drug Metab Dispos 1993 May–Jun; 21(3): 435–40

    PubMed  CAS  Google Scholar 

  19. Lenneras H, Regardh CG. Pharmacokinetics of pafenolol in the rat: a suitable model for studying absorption mechanisms of a drug exhibiting unusual absorption properties in man. Biopharm Drug Dispos 1990 Oct; 11(7): 619–31

    Article  PubMed  CAS  Google Scholar 

  20. Lennernas H, Regardh CG. Dose-dependent intestinal absorption and significant intestinal excretion (exsorption) of the beta-blocker pafenolol in the rat. Pharm Res 1993 May; 10(5): 727–31

    Article  PubMed  CAS  Google Scholar 

  21. Regardh CG, Heggelund A, Kylberg-Hanssen K, et al. Pharmacokinetics of pafenolol after i.v. and oral administration of three separate doses of different strength to man. Biopharm Drug Dispos 1990 Oct; 11(7): 607–17

    CAS  Google Scholar 

  22. Regardh CG, Lundborg P, Gabrielsson M, et al. Pharmacokinetics of a single intravenous and oral dose of pafenolol — a beta 1-adrenoceptor antagonist with atypical absorption and disposition properties — in man. Pharm Res 1990 Dec; 7(12): 1222–7

    Article  PubMed  CAS  Google Scholar 

  23. Lennernas H, Regardh CG. Regional gastrointestinal absorption of the beta-blocker pafenolol in the rat and intestinal transit rate determined by movement of 14C-polyethylene glycol (PEG) 4000. Pharm Res 1993 Jan; 10(1): 130–5

    Article  PubMed  CAS  Google Scholar 

  24. Piquette-Miller M, Jamali F. Effect of adjuvant arthritis on the disposition of acebutolol enantiomers in rats. Agents Actions 1992 Nov; 37(3–4): 290–6

    Article  PubMed  CAS  Google Scholar 

  25. Piquette-Miller M, Jamali F. Pharmacokinetics and multiple peaking of acebutolol enantiomers in rats. Biopharm Drug Dispos 1997 Aug; 18(6): 543–56

    Article  PubMed  CAS  Google Scholar 

  26. Mostafavi SA, Foster RT. Pharmacokinetics of single oral and multiple intravenous and oral administration of acebutolol enantiomers in a rat model. Biopharm Drug Dispos 1998 Oct; 19(7): 425–31

    Article  PubMed  CAS  Google Scholar 

  27. Yamaguchi T, Oida T, Ikeda C, et al. Intestinal absorption of a beta-adrenergic blocking agent nadolol: III. Nuclear magnetic resonance spectroscopic study on nadolol-sodium cholate micellar complex and intestinal absorption of nadolol derivatives in rats. Chem Pharm Bull 1986 Oct; 34(10): 4259–64

    CAS  Google Scholar 

  28. Yamaguchi T, Ikeda C, Sekine Y. Intestinal absorption of a beta-adrenergic blocking agents nadolol: II. Mechanism of the inhibitory effect on the intestinal absorption of nadolol by sodium cholate in rats. Chem Pharm Bull 1986 Sep; 34(9): 3836–43

    CAS  Google Scholar 

  29. Singh K, Orr JM, Abbott FS. Pharmacokinetics and enterohepatic circulation of 2-n-propyl-4-pentenoic acid in the rat. Drug Metab Dispos 1988 Nov–Dec; 16(6): 848–52

    PubMed  CAS  Google Scholar 

  30. Schultz IR, Orner G, Merdink JL, et al. Dose-response relationships and pharmacokinetics of vitellogenin in rainbow trout after intravascular administration of 17alpha-ethynylestradiol. Aquat Toxicol 2001 Jan; 51(3): 305–18

    Article  PubMed  CAS  Google Scholar 

  31. Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990 Jun; 18(6): 472–84

    Article  PubMed  CAS  Google Scholar 

  32. Okusanya O, Forrest A, DiFrancesco R, et al. Compartmental pharmacokinetic analysis of oral amprenavir with secondary peaks. Antimicrob Agents Chemother 2007 May; 51(5): 1822–6

    Article  PubMed  CAS  Google Scholar 

  33. Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001 Dec; 45(12): 3663–8

    Article  PubMed  CAS  Google Scholar 

  34. Sadler BM, Hanson CD, Chittick GE, et al. Safety and pharmacokinetics of amprenavir (141W94), a human immunodeficiency virus (HIV) type 1 protease inhibitor, following oral administration of single doses to HIV-infected adults. Antimicrob Agents Chemother 1999 Jul; 43(7): 1686–92

    PubMed  CAS  Google Scholar 

  35. Kuchimanchi KR, Udata C, Johnston TP, et al. Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats. Drug Metab Dispos 2000 Apr; 28(4): 403–8

    PubMed  CAS  Google Scholar 

  36. Harrison LI, Gibaldi M. Physiologically based pharmacokinetic model for digoxin disposition in dogs and its preliminary application to humans. J Pharm Sci 1977 Dec; 66(12): 1679–83

    Article  PubMed  CAS  Google Scholar 

  37. Gibaldi M. Pharmacokinetics of absorption and elminiation of doxycycline in man. Chemotherapia 1967; 12: 265–71

    Article  CAS  Google Scholar 

  38. Benincosa LJ, Audet PR, Lundberg D, et al. Pharmacokinetics and absolute bioavailability of epristeride in healthy male subjects. Biopharm Drug Dispos 1996 Apr; 17(3): 249–58

    Article  PubMed  CAS  Google Scholar 

  39. Brocks DR, Jamali F. The pharmacokinetics of etodolac enantiomers in the rat: lack of pharmacokinetic interaction between enantiomers. Drug Metab Dispos 1990 Jul–Aug; 18(4): 471–5

    PubMed  CAS  Google Scholar 

  40. Sandberg JA, Eckhoff C, Nau H, et al. Pharmacokinetics of 13-cis-, all-trans-, 13-cis-4-oxo-, and all-trans-4-oxo retinoic acid after intravenous administration in the cynomolgus monkey. Drug Metab Dispos 1994 Jan–Feb; 22(1): 154–60

    PubMed  CAS  Google Scholar 

  41. Colburn WA, Vane FM, Bugge CJ, et al. Pharmacokinetics of 14C-iso-tretinoin in healthy volunteers and volunteers with biliary T-tube drainage. Drug Metab Dispos 1985 May–Jun; 13(3): 327–32

    PubMed  CAS  Google Scholar 

  42. Bischoff KB, Dedrick RL, Zaharko DS, et al. Methotrexate pharmacokinetics. J Pharm Sci 1971 Aug; 60(8): 1128–33

    Article  PubMed  CAS  Google Scholar 

  43. Cremers S, Schoemaker R, Scholten E, et al. Characterizing the role of enterohepatic recycling in the interactions between mycophenolate mofetil and calcineurin inhibitors in renal transplant patients by pharmacokinetic modelling. Br J Clin Pharmacol 2005 Sep; 60(3): 249–56

    Article  PubMed  CAS  Google Scholar 

  44. Premaud A, Debord J, Rousseau A, et al. A double absorption-phase model adequately describes mycophenolic acid plasma profiles in de novo renal transplant recipients given oral mycophenolate mofetil. Clin Pharmacokinet 2005; 44(8): 837–47

    Article  PubMed  CAS  Google Scholar 

  45. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998 Jun; 34(6): 429–55

    Article  PubMed  CAS  Google Scholar 

  46. Cheeseman SH, Hattox SE, McLaughlin MM, et al. Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob Agents Chemother 1993 Feb; 37(2): 178–82

    Article  PubMed  CAS  Google Scholar 

  47. Norris SH, Silverstein HH, George RL, et al. Nevirapine, an HIV-1 reverse transcriptase inhibitor: absorption, distribution and excretion in rats [abstract]. Pharm Res 1992; 9: S263

    Google Scholar 

  48. Piotrovskij VK, Kallay Z, Krejcy K, et al. NG-nitro-L-arginine pharmacokinetics in rats after a single intravascular and oral dose: an appearance of secondary concentration time peaks. Drug Metab Dispos 1993 Sep–Oct; 21(5): 962–4

    PubMed  CAS  Google Scholar 

  49. Piotrovskij V, Kallay Z, Horecky J, et al. Dose-ranging study of NG-nitro-L-arginine pharmacokinetics in rats after bolus intravenous administration. Xenobiotica 1994 Jul; 24(7): 663–9

    Article  PubMed  CAS  Google Scholar 

  50. Shin BS, Kim JJ, Kim J, et al. Oral bioavailability and enterohepatic recirculation of otilonium bromide in rats. Arch Pharm Res 2008 Jan; 31(1): 117–24

    Article  PubMed  CAS  Google Scholar 

  51. Odar-Cederlof I, Vessman J, Alvan G, et al. Oxazepam disposition in uremic patients. Acta Pharmacol Toxicol (Copenh) 1977 Jan; 40 Suppl. 1 (1): 52–62

    Google Scholar 

  52. Alvan G, Odar-Cederlof I. The pharmacokinetic profile of oxazepam. Acta Psychiatr Scand Suppl 1978 (274): 47–55

    Article  PubMed  CAS  Google Scholar 

  53. Mercer HD, Teske RH, Long PE, et al. Drug residues in food animals II: plasma and tissue kinetics of oxytetracycline in young cross-bred swine. J Vet Pharmacol Ther 1978; 1(2): 119–28

    Article  CAS  Google Scholar 

  54. Strandgarden K, Hoglund P, Gronquist L, et al. Absorption and disposition including enterohepatic circulation of (14C) roquinimex after oral administration to healthy volunteers. Biopharm Drug Dispos 2000 Mar; 21(2): 53–67

    Article  PubMed  CAS  Google Scholar 

  55. Strandgarden K, Hoglund P, Nordle O, et al. Dissolution rate-limited absorption and complete bioavailability of roquinimex in man. Biopharm Drug Dispos 1999 Oct; 20(7): 347–54

    Article  PubMed  CAS  Google Scholar 

  56. Adir J. Enterohepatic circulation of tetracycline in rats. J Pharm Sci 1975 Nov; 64(11): 1847–50

    Article  PubMed  CAS  Google Scholar 

  57. Vollmer KO, Liedtke B, Poisson A, et al. Metabolism of thymoxamine: I. Studies with 14C-thymoxamine in rats. Eur J Drug Metab Pharmacokinet 1985 Jan–Mar; 10(1): 61–9

    CAS  Google Scholar 

  58. Gustavson LE, Mengel HB. Pharmacokinetics of tiagabine, a gamma-aminobutyric acid-uptake inhibitor, in healthy subjects after single and multiple doses. Epilepsia 1995 Jun; 36(6): 605–11

    Article  PubMed  CAS  Google Scholar 

  59. Alousi AM, Boinpally R, Wiegand R, et al. A phase 1 trial of XK469: toxicity profile of a selective topoisomerase IIbeta inhibitor. Invest New Drugs 2007 Apr; 25(2): 147–54

    Article  PubMed  CAS  Google Scholar 

  60. Biehl ML, Prelusky DB, Koritz GD, et al. Biliary excretion and enterohepatic cycling of zearalenone in immature pigs. Toxicol Appl Pharmacol 1993 Jul; 121(1): 152–9

    Article  PubMed  CAS  Google Scholar 

  61. Schaiquevich P, Niselman A, Rubio M. Importance of entero-salivary recirculation in paracetamol pharmacokinetics. Biopharm Drug Dispos 2002 Sep; 23(6): 245–9

    Article  PubMed  CAS  Google Scholar 

  62. Ranheim B, Ween H, Egeli AK, et al. Benzathine penicillin G and procaine penicillin G in piglets: comparison of intramuscular and subcutaneous injection. Vet Res Commun 2002 Aug; 26(6): 459–65

    Article  PubMed  CAS  Google Scholar 

  63. Woodings EP, Dixon GT, Harrison C, et al. Ranitidine: a new H2-receptor antagonist. Gut 1980 Mar; 21(3): 187–91

    Article  PubMed  CAS  Google Scholar 

  64. Shim CK, Hong JS. Inter- and intrasubject variations of ranitidine pharmacokinetics after oral administration to normal male subjects. J Pharm Sci 1989 Dec; 78(12): 990–4

    Article  PubMed  CAS  Google Scholar 

  65. Suttle AB, Brouwer KL. Gastrointestinal transit and distribution of ranitidine in the rat. Pharm Res 1995 Sep; 12(9): 1316–22

    Article  PubMed  CAS  Google Scholar 

  66. Reynolds KS, Song MH, Heizer WD, et al. Effect of pancreatico-biliary secretions and GI transit time on the absorption and pharmacokinetic profile of ranitidine in humans. Pharm Res 1998 Aug; 15(8): 1281–5

    Article  PubMed  CAS  Google Scholar 

  67. Schulze JD, Waddington WA, Eli PJ, et al. Concentration-dependent effects of polyethylene glycol 400 on gastrointestinal transit and drug absorption. Pharm Res 2003 Dec; 20(12): 1984–8

    Article  PubMed  CAS  Google Scholar 

  68. Basit AW, Podczeck F, Newton JM, et al. Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine. Pharm Res 2002 Sep; 19(9): 1368–74

    Article  PubMed  CAS  Google Scholar 

  69. Adkin DA, Davis SS, Sparrow RA, et al. The effect of mannitol on the oral bioavailability of cimetidine. J Pharm Sci 1995 Dec; 84(12): 1405–9

    Article  PubMed  CAS  Google Scholar 

  70. Adkin DA, Davis SS, Sparrow RA, et al. The effect of different concentrations of mannitol in solution on small intestinal transit: implications for drug absorption. Pharm Res 1995 Mar; 12(3): 393–6

    Article  PubMed  CAS  Google Scholar 

  71. Henn RM, Isenberg JI, Maxwell V, et al. Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer. N Engl J Med 1975 Aug 21; 293(8): 371–5

    Article  PubMed  CAS  Google Scholar 

  72. Webster J, Barber HE, Hawksworth GM, et al. Cimetidine: a clinical and pharmacokinetic study. Br J Clin Pharmacol 1981 Apr; 11(4): 333–8

    Article  PubMed  CAS  Google Scholar 

  73. Grahnen A, von Bahr C, Lindstrom B, et al. Bioavailability and pharmacokinetics of cimetidine. Eur J Clin Pharmacol 1979 Nov; 16(5): 335–40

    Article  PubMed  CAS  Google Scholar 

  74. Walkenstein SS, Dubb JW, Randolph WC, et al. Bioavailability of cimetidine in man. Gastroenterology 1978 Feb; 74(2 Pt 2): 360–5

    PubMed  CAS  Google Scholar 

  75. Takamatsu N, Welage LS, Hayashi Y, et al. Variability in cimetidine absorption and plasma double peaks following oral administration in the fasted state in humans: correlation with antral gastric motility. Eur J Pharm Biopharm 2002 Jan; 53(1): 37–47

    Article  PubMed  CAS  Google Scholar 

  76. Langguth P, Lee KM, Spahn-Langguth H, et al. Variable gastric emptying and discontinuities in drug absorption profiles: dependence of rates and extent of cimetidine absorption on motility phase and pH. Biopharm Drug Dispos 1994 Dec; 15(9): 719–46

    Article  PubMed  CAS  Google Scholar 

  77. Clements JA, Heading RC, Nimmo WS, et al. Kinetics of acetaminophen absorption and gastric emptying in man. Clin Pharmacol Ther 1978 Oct; 24(4): 420–31

    PubMed  CAS  Google Scholar 

  78. Metsugi Y, Miyaji Y, Ogawara K, et al. Appearance of double peaks in plasma concentration-time profile after oral administration depends on gastric emptying profile and weight function. Pharm Res 2008 Apr; 25(4): 886–95

    Article  PubMed  CAS  Google Scholar 

  79. Wang Y, Roy A, Sun L, et al. A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration. Drug Metab Dispos 1999 Aug; 27(8): 855–9

    PubMed  CAS  Google Scholar 

  80. Ogiso T, Kasutani M, Tanaka H, et al. Pharmacokinetics of epinastine and a possible mechanism for double peaks in oral plasma concentration profiles. Biol Pharm Bull 2001 Jul; 24(7): 790–4

    Article  PubMed  CAS  Google Scholar 

  81. Kim HJ, Bruckner JV, Dallas CE, et al. Effect of dosing vehicles on the pharmacokinetics of orally administered carbon tetrachloride in rats. Toxicol Appl Pharmacol 1990 Jan; 102(1): 50–60

    Article  PubMed  CAS  Google Scholar 

  82. Robertson DR, Renwick AG, Macklin B, et al. The influence of levodopa on gastric emptying in healthy elderly volunteers. Eur J Clin Pharmacol 1992; 42(4): 409–12

    PubMed  CAS  Google Scholar 

  83. Brockmeier D, Grigoleit HG, Heptner H, et al. Kinetics of piretanide absorption from the gastrointestinal tract. Methods Find Exp Clin Pharmacol 1986 Dec; 8(12): 731–9

    PubMed  CAS  Google Scholar 

  84. Chang RK, Shojaei AH. Effect of a lipoidic excipient on the absorption profile of compound UK 81252 in dogs after oral administration. J Pharm Pharm Sci 2004 Jan 23; 7(1): 8–12

    PubMed  CAS  Google Scholar 

  85. Charman WN, Rogge MC, Boddy AW, et al. Absorption of danazol after administration to different sites of the gastrointestinal tract and the relationship to single- and double-peak phenomena in the plasma profiles. J Clin Pharmacol 1993 Dec; 33(12): 1207–13

    PubMed  CAS  Google Scholar 

  86. Charman WN, Rogge MC, Boddy AW, et al. Effect of food and a monoglyceride emulsion formulation on danazol bioavailability. J Clin Pharmacol 1993 Apr; 33(4): 381–6

    PubMed  CAS  Google Scholar 

  87. Bergstrom RF, Kay DR, Harkcom TM, et al. Penicillamine kinetics in normal subjects. Clin Pharmacol Ther 1981 Sep; 30(3): 404–13

    Article  PubMed  CAS  Google Scholar 

  88. Bergstrom RF, Kay RD, Wagner JG. The pharmacokinetics of penicillamine in a female mongrel dog. J Pharmacokinet Biopharm 1981 Oct; 9(5): 603–21

    PubMed  CAS  Google Scholar 

  89. Brocks DR, Upward JW, Georgiou P, et al. The single and multiple dose pharmacokinetics of pranlukast in healthy volunteers. Eur J Clin Pharmacol 1996; 51(3–4): 303–8

    Article  PubMed  CAS  Google Scholar 

  90. Kenyon CJ, Brown F, McClelland GR, et al. The use of pharmacoscintigraphy to elucidate food effects observed with a novel protease inhibitor (saquinavir). Pharm Res 1998 Mar; 15(3): 417–22

    Article  PubMed  CAS  Google Scholar 

  91. Sternieri E, Pinetti D, Coccia CP, et al. Pharmacokinetics of sumatriptan in non-respondent and in adverse drug reaction reporting migraine patients. J Headache Pain 2005 Sep; 6(4): 319–21

    Article  PubMed  CAS  Google Scholar 

  92. Moore KH, Hussey EK, Shaw S, et al. Safety, tolerability, and pharmacokinetics of sumatriptan in healthy subjects following ascending single intranasal doses and multiple intranasal doses. Cephalalgia 1997 Jun; 17(4): 541–50

    Article  PubMed  CAS  Google Scholar 

  93. Molz KH, Pabst G, Dilger C, et al. Multiple peaks and low bioavailability of furosemide correlate with the volume of fluid ingested. Eur J Drug Metab Pharmacokinet 1991; spec. no. 3: 194–200

    Google Scholar 

  94. Hammarlund MM, Paalzow LK, Odlind B. Pharmacokinetics of furosemide in man after intravenous and oral administration: application of moment analysis. Eur J Clin Pharmacol 1984; 26(2): 197–207

    Article  PubMed  CAS  Google Scholar 

  95. Milne L, Williams NE, Calvey TN, et al. Plasma concentration and metabolism of phenoperidine in man. Br J Anaesth 1980 May; 52(5): 537–40

    Article  PubMed  CAS  Google Scholar 

  96. Fischler M, Levron JC, Trang H, et al. Pharmacokinetics of phenoperidine in anaesthetized patients undergoing general surgery. Br J Anaesth 1985 Sep; 57(9): 872–6

    Article  PubMed  CAS  Google Scholar 

  97. Calvey TN, Milne LA, Williams NE, et al. Effect of antacids on the plasma concentration of phenoperidine. Br J Anaesth 1983 Jun; 55(6): 535–9

    Article  PubMed  CAS  Google Scholar 

  98. McQuay HJ, Moore RA, Paterson GM, et al. Plasma fentanyl concentrations and clinical observations during and after operation. Br J Anaesth 1979 Jun; 51(6): 543–50

    Article  PubMed  CAS  Google Scholar 

  99. Stoeckel H, Hengstmann JH, Schuttler J. Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression. Br J Anaesth 1979 Aug; 51(8): 741–5

    Article  PubMed  CAS  Google Scholar 

  100. Fung DL, Eisele JH. Fentanyl pharmacokinetics in awake volunteers. J Clin Pharmacol 1980 Nov–Dec; 20(11–12): 652–8

    PubMed  CAS  Google Scholar 

  101. Bovill JG, Sebel PS. Pharmacokinetics of high-dose fentanyl: a study in patients undergoing cardiac surgery. Br J Anaesth 1980 Aug; 52(8): 795–801

    Article  PubMed  CAS  Google Scholar 

  102. Bower S, Hull CJ. Comparative pharmacokinetics of fentanyl and alfentanil. Br J Anaesth 1982 Aug; 54(8): 871–7

    Article  PubMed  CAS  Google Scholar 

  103. Bressolle F, Gomeni R, Alric R, et al. A double Weibull input function describes the complex absorption of sustained-release oral sodium valproate. J Pharm Sci 1994 Oct; 83(10): 1461–4

    Article  PubMed  CAS  Google Scholar 

  104. Yeomans ND, Vajda FJ, Baldas J. Bioavailability of valproate after gastric and direct intestinal administration in rats. Clin Exp Pharmacol Physiol 1982 Mar–Apr; 9(2): 173–7

    Article  PubMed  CAS  Google Scholar 

  105. Murata K, Noda K, Kohno K, et al. Pharmacokinetic analysis of concentration data of drugs with irregular absorption profiles using multifraction absorption models. J Pharm Sci 1987 Feb; 76(2): 109–13

    Article  PubMed  CAS  Google Scholar 

  106. Murata K, Noda K. Pharmacokinetic analysis of an oral sustained-release diltiazem preparation using multifraction absorption models. Pharm Res 1993 May; 10(5): 757–62

    Article  PubMed  CAS  Google Scholar 

  107. Murata K, Yamahara H, Kobayashi M, et al. Pharmacokinetics of an oral sustained-release diltiazem preparation. J Pharm Sci 1989 Nov; 78(11): 960–3

    Article  PubMed  CAS  Google Scholar 

  108. Murata K, Noda K. Pharmacokinetics of multiparticulate sustained-release diltiazem preparations in dogs. J Pharm Sci 1994 Jan; 83(1): 38–41

    Article  PubMed  CAS  Google Scholar 

  109. Williams MF, Dukes GE, Heizer W, et al. Influence of gastrointestinal site of drug delivery on the absorption characteristics of ranitidine. Pharm Res 1992 Sep; 9(9): 1190–4

    Article  PubMed  CAS  Google Scholar 

  110. Schaiquevich P, Niselman A, Rubio M. Comparison of two compartmental models for describing ranitidine’s plasmatic profiles. Pharmacol Res 2002 May; 45(5): 399–405

    Article  PubMed  CAS  Google Scholar 

  111. Suttle AB, Brouwer KL. Bile flow but not enterohepatic recirculation influences the pharmacokinetics of ranitidine in the rat. Drug Metab Dispos 1994 Mar–Apr; 22(2): 224–32

    PubMed  CAS  Google Scholar 

  112. van Hecken AM, Tjandramaga TB, Mullie A, et al. Ranitidine: single dose pharmacokinetics and absolute bioavailability in man. Br J Clin Pharmacol 1982 Aug; 14(2): 195–200

    Article  PubMed  Google Scholar 

  113. Mummaneni V, Dressman JB. Intestinal uptake of cimetidine and ranitidine in rats. Pharm Res 1994 Nov; 11(11): 1599–604

    Article  PubMed  CAS  Google Scholar 

  114. Garg DC, Weidler DJ, Eshelman FN. Ranitidine bioavailability and kinetics in normal male subjects. Clin Pharmacol Ther 1983 Apr; 33(4): 445–52

    Article  PubMed  CAS  Google Scholar 

  115. Witcher JW, Boudinot FD. Applications and simulations of a discontinuous oral absorption pharmacokinetic model. Pharm Res 1996 Nov; 13(11): 1720–4

    Article  PubMed  CAS  Google Scholar 

  116. Plusquellec Y, Efthymiopoulos C, Duthil P, et al. A pharmacokinetic model for multiple sites discontinuous gastrointestinal absorption. Med Eng Phys 1999 Oct; 21(8): 525–32

    Article  PubMed  CAS  Google Scholar 

  117. Efthymiopoulos C. Discontinous absorption of ranitidine [abstract]. 9th Annual Meeting of the American Association of Pharmaceutical Scientists; 1994 Nov 6–10; San Diego (CA)

    Google Scholar 

  118. Miller R. Pharmacokinetics and bioavailability of ranitidine in humans. J Pharm Sci 1984 Oct; 73(10): 1376–9

    Article  PubMed  CAS  Google Scholar 

  119. Gramatte T, el Desoky E, Klotz U. Site-dependent small intestinal absorption of ranitidine. Eur J Clin Pharmacol 1994; 46(3): 253–9

    Article  PubMed  CAS  Google Scholar 

  120. Brockmeier D, Grigoleit HG, Leonhardt H. Absorption of glibenclamide from different sites of the gastro-intestinal tract. Eur J Clin Pharmacol 1985; 29(2): 193–7

    Article  PubMed  CAS  Google Scholar 

  121. Bodemar G, Norlander B, Fransson L, et al. The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine: studies in patients with peptic ulcer disease. Br J Clin Pharmacol 1979 Jan; 7(1): 23–31

    Article  PubMed  CAS  Google Scholar 

  122. Guay DR, Matzke GR, Bockbrader HN, et al. Comparison of bioavailability and pharmacokinetics of cimetidine in subjects with normal and impaired renal function. Clin Pharm 1983 Mar–Apr; 2(2): 157–62

    PubMed  CAS  Google Scholar 

  123. Staveris S, Houin G, Tillement JP, et al. Primary dose-dependent pharmacokinetic study of veralipride. J Pharm Sci 1985 Jan; 74(1): 94–6

    Article  PubMed  CAS  Google Scholar 

  124. Staveris S, Plusquellec Y, Campistron G, et al. Pharmacokinetics of veralipride after chronic administration in humans. J Pharm Sci 1988 Jan; 77(1): 64–7

    Article  PubMed  CAS  Google Scholar 

  125. Staveris S, Houin G, Dufour A, et al. Evidence for a second site of absorption of veralipride in the human small intestine: use of a new drug delivery telemetric shuttle. Arzneimittelforschung 1994 Sep; 44(9): 1068–72

    PubMed  CAS  Google Scholar 

  126. Plusquellec Y, Campistron G, Staveris S, et al. A double-peak phenomenon in the pharmacokinetics of veralipride after oral administration: a double-site model for drug absorption. J Pharmacokinet Biopharm 1987 Jun; 15(3): 225–39

    PubMed  CAS  Google Scholar 

  127. Plusquellec Y, Houin G. Pharmacokinetic compartmental model with n sites of absorption along the gastrointestinal tract. Arzneimittelforschung 1994 May; 44(5): 679–82

    PubMed  CAS  Google Scholar 

  128. Wright JD, Ma T, Chu CK, et al. Discontinuous oral absorption pharmacokinetic model and bioavailability of 1-(2-fluoro-5-methyl-beta-L-arabi-nofuranosyl)uracil (L-FMAU) in rats. Biopharm Drug Dispos 1996 Apr; 17(3): 197–207

    Article  PubMed  CAS  Google Scholar 

  129. Issar M, Singh SK, Mishra B, et al. Pharmacokinetics, in-situ absorption and protein binding studies of a new neuroleptic agent centbutindole in rats. Eur J Pharm Sci 2003 Jun; 19(2–3): 105–13

    Article  PubMed  CAS  Google Scholar 

  130. Tubic M, Wagner D, Spahn-Langguth H, et al. Effects of controlled-release on the pharmacokinetics and absorption characteristics of a compound undergoing intestinal efflux in humans. Eur J Pharm Sci 2006 Nov; 29(3–4): 231–9

    Article  PubMed  CAS  Google Scholar 

  131. Siegmund W, Ludwig K, Engel G, et al. Variability of intestinal expression of P-glycoprotein in healthy volunteers as described by absorption of talinolol from four bioequivalent tablets. J Pharm Sci 2003 Mar; 92(3): 604–10

    Article  PubMed  CAS  Google Scholar 

  132. Wetterich U, Spahn-Langguth H, Mutschler E, et al. Evidence for intestinal secretion as an additional clearance pathway of talinolol enantiomers: concentration-and dose-dependent absorption in vitro and in vivo. Pharm Res 1996 Apr; 13(4): 514–22

    Article  PubMed  CAS  Google Scholar 

  133. Terhaag B, Gramatte T, Richter K, et al. The biliary elimination of the selective beta-receptor blocking drug talinolol in man. Int J Clin Pharmacol Ther Toxicol 1989 Apr; 27(4): 170–2

    PubMed  CAS  Google Scholar 

  134. Gaffield W. Circular dichroism, optical rotatory dispersion and absolute configuration of flavanones 3-hydroxyflavanones and their glycosides determination of aglycone chirality in flavanone glycosides. Tetrahedron 1970; 26: 4093–108

    Article  CAS  Google Scholar 

  135. Saghir SA, Schultz IR. Low-dose pharmacokinetics and oral bioavailability of dichloroacetate in naive and GST-zeta-depleted rats. Environ Health Perspect 2002 Aug; 110(8): 757–63

    Article  PubMed  CAS  Google Scholar 

  136. Saghir SA, Schultz IR. Toxicokinetics and oral bioavailability of halogenated acetic acids mixtures in naive and GSTzeta-depleted rats. Toxicol Sci 2005 Apr; 84(2): 214–24

    Article  PubMed  CAS  Google Scholar 

  137. Schultz IR, Merdink JL, Gonzalez-Leon A, et al. Comparative toxicokinetics of chlorinated and brominated haloacetates in F344 rats. Toxicol Appl Pharmacol 1999 Jul 15; 158(2): 103–14

    Article  PubMed  CAS  Google Scholar 

  138. Imbimbo BP, Daniotti S, Vidi A, et al. Discontinuous oral absorption of cimetropium bromide, a new antispasmodic drug. J Pharm Sci 1986 Jul; 75(7): 680–4

    Article  PubMed  CAS  Google Scholar 

  139. Riond JL, Riviere JE. Pharmacokinetics and metabolic inertness of doxycycline in young pigs. Am J Vet Res 1990 Aug; 51(8): 1271–5

    PubMed  CAS  Google Scholar 

  140. Fabre J, Pitton JS, Kunz JP. Distribution and excretion of doxycycline in man. Chemotherapy 1966; 11(2): 73–85

    Article  PubMed  CAS  Google Scholar 

  141. Malmborg AS. Bioavailability of doxycycline monohydrate: a comparison with equivalent doses of doxycycline hydrochloride. Chemotherapy 1984; 30(2): 76–80

    Article  PubMed  CAS  Google Scholar 

  142. Schmitt H, Batz G, Knoll R, et al. Plasma level changes of fentanyl and midazolam after release of a prolonged thigh tourniquet. Acta Anaesthesiol Scand 1990 Feb; 34(2): 104–8

    Article  PubMed  CAS  Google Scholar 

  143. Friedrich LV, White RL, Brundage DM, et al. The effect of tourniquet inflation on cefazolin tissue penetration during total knee arthroplasty. Pharmacotherapy 1990; 10(6): 373–7

    PubMed  CAS  Google Scholar 

  144. Barnette RE, Eriksson LI, Cooney GF, et al. Sequestration of vecuronium bromide during extremity surgery involving use of a pneumatic tourniquet. Acta Anaesthesiol Scand 1997 Jan; 41(1 Pt 1): 49–54

    Article  PubMed  CAS  Google Scholar 

  145. Hudson RJ, Bergstrom RG, Thomson IR, et al. Pharmacokinetics of sufentanil in patients undergoing abdominal aortic surgery. Anesthesiology 1989 Mar; 70(3): 426–31

    Article  PubMed  CAS  Google Scholar 

  146. Amidon GL, Lennernas H, Shah VP, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995 Mar; 12(3): 413–20

    Article  PubMed  CAS  Google Scholar 

  147. Gibaldi M. Pharmacokinetics of absorption and elimination of doxycycline in man. Chemotherapia 1967; 12: 265–71

    Article  CAS  Google Scholar 

  148. Fabre J, Milek E, Kalfopoulos P, et al. Tetracycline kinetics in man: digestive absorption and serum concentration. Schweiz Med Wochenschr 1971 May 1; 101(17): 593–8

    PubMed  CAS  Google Scholar 

  149. Fabre J, Kunz JP, Virieux C, et al. The behavior of doxycycline in man. Chemotherapy 1968; 13 Suppl.: 23-40

    Google Scholar 

  150. Pedersen PV, Miller R. Pharmacokinetics of doxycycline reabsorption. J Pharm Sci 1980 Feb; 69(2): 204–7

    Article  PubMed  CAS  Google Scholar 

  151. Schach VWM, Schachaavonwittenau M, Twomey TM, et al. The disposition of doxycycline by the rat. Chemotherapy 1972; 17(1): 26–39

    Article  Google Scholar 

  152. Whelton A, Schach von Wittenau M, Twomey TM, et al. Doxycycline pharmacokinetics in the absence of renal function. Kidney Int 1974 May; 5(5): 365–71

    Article  PubMed  CAS  Google Scholar 

  153. Riviere JE. Veterinary clinical pharmacokinetics II: modeling. Compend Contin Educ Practic Vet 1988; 10: 314–28

    Google Scholar 

  154. Heggelund A, Jansson C, Lundborg P, et al. The effect of food on the gastrointestinal absorption of pafenolol: a preliminary study. Hassle Rep 1982; 206-778: 1-10

    Google Scholar 

  155. Piquette-Miller M, Foster RT, Kappagoda CT, et al. Pharmacokinetics of acebutolol enantiomers in humans. J Pharm Sci 1991 Apr; 80(4): 313–6

    Article  PubMed  CAS  Google Scholar 

  156. Mostafavi SA, Foster RT. Pharmacokinetics of acebutolol enantiomers after intravenous administration of racemate in a rat model: a dosing range comparison. Biopharm Drug Dispos 1997 Jul; 18(5): 397–408

    Article  PubMed  CAS  Google Scholar 

  157. Mostafavi SA, Foster RT. Influence of cimetidine co-administration on the pharmacokinetics of acebutolol enantiomers and its metabolite diacetolol in a rat model: the effect of gastric pH on double-peak phenomena. Int J Pharm 2003 Apr 14; 255(1–2): 81–6

    Article  PubMed  CAS  Google Scholar 

  158. Grosvenor MP, Lofroth JE. Interaction between bile salts and beta-adrenoceptor antagonists. Pharm Res 1995 May; 12(5): 682–6

    Article  PubMed  CAS  Google Scholar 

  159. Murata K, Yamahara H, Noda K. Pharmacokinetics of diltiazem and its metabolites in dogs after oral administration of a multiparticulate sustained-release preparation. Pharm Res 1993 Aug; 10(8): 1165–8

    Article  PubMed  CAS  Google Scholar 

  160. Roberts MS, Magnusson BM, Burczynski FJ, et al. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 2002; 41(10): 751–90

    Article  PubMed  CAS  Google Scholar 

  161. Steimer JL, Plusquellec Y, Guillaume A, et al. A time-lag model for pharmacokinetics of drugs subject to enterohepatic circulation. J Pharm Sci 1982 Mar; 71(3): 297–302

    Article  PubMed  CAS  Google Scholar 

  162. Chen HS, Gross JF. Pharmacokinetics of drugs subject to enterohepatic circulation. J Pharm Sci 1979 Jun; 68(6): 792–4

    Article  PubMed  CAS  Google Scholar 

  163. Shou M, Lu W, Kari PH, et al. Population pharmacokinetic modeling for enterohepatic recirculation in Rhesus monkey. Eur J Pharm Sci 2005 Oct; 26(2): 151–61

    Article  PubMed  CAS  Google Scholar 

  164. Shepard TA, Lockwood GF, Aarons LJ, et al. Mean residence time for drugs subject to enterohepatic cycling. J Pharmacokinet Biopharm 1989 Jun; 17(3): 327–45

    PubMed  CAS  Google Scholar 

  165. Tse FL, Ballard F, Skinn J. Estimating the fraction reabsorbed in drugs undergoing enterohepatic circulation. J Pharmacokinet Biopharm 1982 Aug; 10(4): 455–61

    PubMed  CAS  Google Scholar 

  166. Laurent A, Alary J, Debrauwer L, et al. Analysis in the rat of 4-hydroxynonenal metabolites excreted in bile: evidence of enterohepatic circulation of these byproducts of lipid peroxidation. Chem Res Toxicol 1999 Oct; 12(10): 887–94

    Article  PubMed  CAS  Google Scholar 

  167. Dahlstrom BE, Paalzow LK. Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat. J Pharmacokinet Biopharm 1978 Dec; 6(6): 505–19

    PubMed  CAS  Google Scholar 

  168. Jacqz E, Ward S, Johnson R, et al. Extrahepatic glucuronidation of morphine in the dog. Drug Metab Dispos 1986 Nov–Dec; 14(6): 627–30

    PubMed  CAS  Google Scholar 

  169. Hasselstrom J, Sawe J. Morphine pharmacokinetics and metabolism in humans: enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 1993 Apr; 24(4): 344–54

    Article  PubMed  CAS  Google Scholar 

  170. Hanks GW, Wand PJ. Enterohepatic circulation of opioid drugs: is it clinically relevant in the treatment of cancer patients?. Clin Pharmacokinet 1989 Aug; 17(2): 65–8

    Article  PubMed  CAS  Google Scholar 

  171. Westerling D, Frigren L, Hoglund P. Morphine pharmacokinetics and effects on salivation and continuous reaction times in healthy volunteers. Ther Drug Monit 1993 Oct; 15(5): 364–74

    Article  PubMed  CAS  Google Scholar 

  172. Ezzet F, Krishna G, Wexler DB, et al. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther 2001 Jun; 23(6): 871–85

    Article  PubMed  CAS  Google Scholar 

  173. van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 2000 Apr; 129(8): 1748–54

    Article  PubMed  Google Scholar 

  174. Hobbs DC. Pharmacokinetics of piroxicam in man. Eur J Rheumatol Inflamm 1983; 6(1): 46–55

    PubMed  CAS  Google Scholar 

  175. Prescilla RP, Frattarelli DA, Haritos D, et al. Pharmacokinetics of rofecoxib in children with sickle cell hemoglobinopathy. J Pediatr Hematol Oncol 2004 Oct; 26(10): 661–4

    Article  PubMed  Google Scholar 

  176. Halpin RA, Porras AG, Geer LA, et al. The disposition and metabolism of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in human subjects. Drug Metab Dispos 2002 Jun; 30(6): 684–93

    Article  PubMed  CAS  Google Scholar 

  177. Baillie TA, Halpin RA, Matuszewski BK, et al. Mechanistic studies on the reversible metabolism of rofecoxib to 5-hydroxyrofecoxib in the rat: evidence for transient ring opening of a substituted 2-furanone derivative using stable isotope-labeling techniques. Drug Metab Dispos 2001 Dec; 29(12): 1614–28

    PubMed  CAS  Google Scholar 

  178. Scatina JA, Hicks DR, Kraml M, et al. Disposition of a new tetra-hydrocarbazole analgesic drug in laboratory animals and man. Xenobiotica 1989 Sep; 19(9): 991–1002

    Article  PubMed  CAS  Google Scholar 

  179. Hucker HB, Kwan KC, Duggan DE. Pharmacokinetics and metabolism of non-steroidal anti-inflammatory drugs. In: Bridges JW, Chasseaud LF, editors. Progress in drug metabolism. 5th ed. Chichester: Wiley, 1980: 165–253

    Google Scholar 

  180. Duggan DE, Hooke KF, Noll RM, et al. Comparative disposition of sulindac and metabolites in five species. Biochem Pharmacol 1978; 27(19): 2311–20

    Article  PubMed  CAS  Google Scholar 

  181. Illing HP, Fromson JM. Species differences in the disposition and metabolism of 6,11-dihydro-11-oxodibenz[be]oxepin-2-acetic acid (isoxepac) in rat, rabbit, dog, rhesus monkey, and man. Drug Metab Dispos 1978 Sep–Oct; 6(5): 510–7

    PubMed  CAS  Google Scholar 

  182. Brocks DR, Jamali F, Russell AS, et al. The stereoselective pharmacokinetics of etodolac in young and elderly subjects, and after cholecystectomy. J Clin Pharmacol 1992; 32(11): 982–9

    PubMed  CAS  Google Scholar 

  183. Escher M, Daali Y, Chabert J, et al. Pharmacokinetic and pharmacodynamic properties of buprenorphine after a single intravenous administration in healthy volunteers: a randomized, double-blind, placebo-controlled, crossover study. Clin Ther 2007 Aug; 29(8): 1620–31

    Article  PubMed  CAS  Google Scholar 

  184. Ohtani M, Kotaki H, Uchino K, et al. Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbuprenorphine, in rats. Drug Metab Dispos 1994 Jan–Feb; 22(1): 2–7

    PubMed  CAS  Google Scholar 

  185. Cone EJ, Gorodetzky CW, Yousefnejad D, et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos 1984 Sep–Oct; 12(5): 577–81

    PubMed  CAS  Google Scholar 

  186. Brewster D, Humphrey MJ, McLeavy MA. Biliary excretion, metabolism and enterohepatic circulation of buprenorphine. Xenobiotica 1981 Mar; 11(3): 189–96

    Article  PubMed  CAS  Google Scholar 

  187. Audet PR, Baine NH, Benincosa LJ, et al. Epristeride steroid 5a-reductase inhibitor treatment for benign prostatic hyperplasia. Drugs Future 1994; 19: 646–50

    Google Scholar 

  188. Rad M, Humpel M, Schaefer O, et al. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women. Br J Clin Pharmacol 2006 Sep; 62(3): 288–96

    Article  PubMed  CAS  Google Scholar 

  189. Ichikawa T, Ishida S, Sakiya Y, et al. Biliary excretion and enterohepatic cycling of glycyrrhizin in rats. J Pharm Sci 1986 Jul; 75(7): 672–5

    Article  PubMed  CAS  Google Scholar 

  190. Ishida S, Sakiya Y, Ichikawa T, et al. Prediction of glycyrrhizin disposition in rat and man by a physiologically based pharmacokinetic model. Chem Pharm Bull 1990 Jan; 38(1): 212–8

    Article  PubMed  CAS  Google Scholar 

  191. Rondelli I, Acerbi D, Ventura P. Steady-state pharmacokinetics of ipriflavone and its metabolites in patients with renal failure. Int J Clin Pharmacol Res 1991; 11(4): 183–92

    PubMed  CAS  Google Scholar 

  192. Yoshida K, Tsukamoto T, Torii H, et al. Disposition of ipriflavone (TC-80) in rats and dogs. Radioisotopes 1985 Nov; 34(11): 618–23

    Article  PubMed  CAS  Google Scholar 

  193. Joshi JV, Vaidya RA, Pandey SN, et al. Plasma levels of genistein following a single dose of soy extract capsule in Indian women. Indian J Med Res 2007 Apr; 125(4): 534–41

    PubMed  CAS  Google Scholar 

  194. Xu X, Harris KS, Wang HJ, et al. Bioavailability of soybean isoflavones depends upon gut microflora in women. J Nutr 1995 Sep; 125(9): 2307–15

    PubMed  CAS  Google Scholar 

  195. Setchell KD, Brown NM, Desai PB, et al. Bioavailability, disposition, and dose-response effects of soy isoflavones when consumed by healthy women at physiologically typical dietary intakes. J Nutr 2003 Apr; 133(4): 1027–35

    PubMed  CAS  Google Scholar 

  196. Rowland I, Faughnan M, Hoey L, et al. Bioavailability of phyto-oestrogens. Br J Nutr 2003 Jun; 89 Suppl. 1: S45–58

    PubMed  CAS  Google Scholar 

  197. O’Dwyer PJ, Szarka C, Brennan JM, et al. Pharmacokinetics of the chemopreventive agent oltipraz and of its metabolite M3 in human subjects after a single oral dose. Clin Cancer Res 2000 Dec; 6(12): 4692–6

    PubMed  Google Scholar 

  198. Bieder A, Decouvelaere B, Gaillard C, et al. Comparison of the metabolism of oltipraz in the mouse, rat and monkey and in man: distribution of the metabolites in each species. Arzneimittelforschung 1983; 33(9): 1289–97

    PubMed  CAS  Google Scholar 

  199. Gupta E, Olopade OI, Ratain MJ, et al. Pharmacokinetics and pharmacodynamics of oltipraz as a chemopreventive agent. Clin Cancer Res 1995 Oct; 1(10): 1133–8

    PubMed  CAS  Google Scholar 

  200. Liu Y, Liu Y, Dai Y, et al. Enteric disposition and recycling of flavonoids and ginkgo flavonoids. J Altern Complement Med 2003 Oct; 9(5): 631–40

    Article  PubMed  Google Scholar 

  201. Kochak GM, Mason WD. The pharmacokinetics of alpha-methyldopa in dogs. J Pharmacokinet Biopharm 1985 Aug; 13(4): 405–23

    PubMed  CAS  Google Scholar 

  202. Kwan KC, Foltz EL, Breault GO, et al. Pharmacokinetics of methyldopa in man. J Pharmacol Exp Ther 1976 Aug; 198(2): 264–77

    PubMed  CAS  Google Scholar 

  203. Plusquellec Y, Arnaud R, Saivin S, et al. Enterohepatic recirculation of the new antihypertensive drug UP 269-6 in humans: a possible model to account for multiple plasma peaks. Arzneimittelforschung 1998 Feb; 48(2): 138–44

    PubMed  CAS  Google Scholar 

  204. Crevoisier C, Delisle MC, Joseph I, et al. Comparative single-dose pharmacokinetics of clonazepam following intravenous, intramuscular and oral administration to healthy volunteers. Eur Neurol 2003; 49(3): 173–7

    Article  PubMed  CAS  Google Scholar 

  205. Eschenhof E. Studies on the disposition of the anticonvulsant clonazepam in the organisms of rat, dog, and man. Arzneimittelforschung 1973 Mar; 23(3): 390–400

    PubMed  CAS  Google Scholar 

  206. Berlin A, Dahlstrom H. Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol 1975 Dec 19; 9(2–3): 155–9

    Article  PubMed  CAS  Google Scholar 

  207. Greenblatt DJ, Harmatz JS, Dorsey C, et al. Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo. Clin Pharmacol Ther 1988 Sep; 44(3): 326–34

    Article  PubMed  CAS  Google Scholar 

  208. Jeong EJ, Liu X, Jia X, et al. Coupling of conjugating enzymes and efflux transporters: impact on bioavailability and drug interactions. Curr Drug Metab 2005 Oct; 6(5): 455–68

    Article  PubMed  CAS  Google Scholar 

  209. Kutchai HC. The gastrointestinal system. In: Berne RM, Levy MN, editors. Physiology. 4th ed. St Louis (MO): Mosby, 1998: 589–674

    Google Scholar 

  210. Sarna SK. Cyclic motor activity; migrating motor complex. Gastroenterology 1985 Oct; 89(4): 894–913

    PubMed  CAS  Google Scholar 

  211. Hebbard GS, Sun WM, Bochner F, et al. Pharmacokinetic considerations in gastrointestinal motor disorders. Clin Pharmacokinet 1995 Jan; 28(1): 41–66

    Article  PubMed  CAS  Google Scholar 

  212. Oberle RL, Amidon GL. The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon. J Pharmacokinet Biopharm 1987 Oct; 15(5): 529–44

    PubMed  CAS  Google Scholar 

  213. Schulze JD, Ashiru DA, Khela MK, et al. Impact of formulation excipients on human intestinal transit. J Pharm Pharmacol 2006 Jun; 58(6): 821–5

    Article  PubMed  CAS  Google Scholar 

  214. Basit AW, Newton JM, Short MD, et al. The effect of polyethylene glycol 400 on gastrointestinal transit: implications for the formulation of poorly-water soluble drugs. Pharm Res 2001 Aug; 18(8): 1146–50

    Article  PubMed  CAS  Google Scholar 

  215. Koch KM, Parr AF, Tomlinson JJ, et al. Effect of sodium acid pyrophosphate on ranitidine bioavailability and gastrointestinal transit time. Pharm Res 1993 Jul; 10(7): 1027–30

    Article  PubMed  CAS  Google Scholar 

  216. Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res 2004 Feb; 21(2): 201–30

    Article  PubMed  CAS  Google Scholar 

  217. Pedersen PV, Miller R. Pharmacokinetics and bioavailability of cimetidine in humans. J Pharm Sci 1980 Apr; 69(4): 394–8

    Article  PubMed  CAS  Google Scholar 

  218. Veng Pedersen P. Pharmacokinetic analysis by linear system approach I: cimetidine bioavailability and second peak phenomenon. J Pharm Sci 1981 Jan; 70(1): 32–8

    Article  PubMed  CAS  Google Scholar 

  219. Spence RW, Celestin LR, de la Guardia R, et al. Biliary secretion of cimetidine in man. 2nd International Symposium on Histamine H2-Receptor Antagonists; Amsterdam; 1977

  220. Somogyi A, Gugler R. Clinical pharmacokinetics of cimetidine. Clin Pharmacokinet 1983 Nov–Dec; 8(6): 463–95

    Article  PubMed  CAS  Google Scholar 

  221. Nimmo J, Heading RC, Tothill P, et al. Pharmacological modification of gastric emptying: effects of propantheline and metoclopromide on paracetamol absorption. BMJ 1973 Mar 10; 1(5853): 587–9

    Article  PubMed  CAS  Google Scholar 

  222. Adkin DA, Davis SS, Sparrow RA, et al. The effects of pharmaceutical excipients on small intestinal transit. Br J Clin Pharmacol 1995 Apr; 39(4): 381–7

    Article  PubMed  CAS  Google Scholar 

  223. Brocks DR, Upward J, Davy M, et al. Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers. Br J Clin Pharmacol 1997 Sep; 44(3): 289–91

    Article  PubMed  CAS  Google Scholar 

  224. Aurora S, Kori S, Barrodale P, et al. Gastric stasis occurs in spontaneous, visually induced, and interictal migraine. Headache 2007 Nov–Dec; 47(10): 1443–6

    PubMed  Google Scholar 

  225. Moro E, Crema F, De Ponti F, et al. Triptans and gastric accommodation: pharmacological and therapeutic aspects. Dig Liver Dis 2004 Jan; 36(1): 85–92

    Article  PubMed  CAS  Google Scholar 

  226. Ferrari A, Pinetti D, Bertolini A, et al. Interindividual variability of oral sumatriptan pharmacokinetics and of clinical response in migraine patients. Eur J Clin Pharmacol 2008 May; 64(5): 489–95

    Article  PubMed  CAS  Google Scholar 

  227. Higaki K, Choe SY, Lobenberg R, et al. Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans. Eur J Pharm Biopharm 2008 Sep; 70(1): 313–25

    Article  PubMed  CAS  Google Scholar 

  228. Pal A, Brasseur JG, Abrahamsson B. A stomach road or ‘Magenstrasse’ for gastric emptying. J Biomech 2007; 40(6): 1202–10

    Article  PubMed  Google Scholar 

  229. Chau NP, Zech PY, Pozet N, et al. Ranitidine kinetics in normal subjects. Clin Pharmacol Ther 1982 Jun; 31(6): 770–4

    Article  PubMed  CAS  Google Scholar 

  230. Lebert PA, MacLeod SM, Mahon WA, et al. Ranitidine kinetics and dynamics: I. Oral dose studies. Clin Pharmacol Ther 1981 Oct; 30(4): 539–44

    Article  CAS  Google Scholar 

  231. McNeil JJ, Mihaly GW, Anderson A, et al. Pharmacokinetics of the H2-receptor antagonist ranitidine in man. Br J Clin Pharmacol 1981 Sep; 12(3): 411–5

    Article  PubMed  CAS  Google Scholar 

  232. Mignon M, Chau NP, Nguyen-Phuoc BK, et al. Ranitidine upon mealinduced gastric secretion: oral pharmacokinetics and plasma concentration effect relationships. Br J Clin Pharmacol 1982 Aug; 14(2): 187–93

    Article  PubMed  CAS  Google Scholar 

  233. Okolicsanyi L, Venuti M, Strazzabosco M, et al. Oral and intravenous pharmacokinetics of ranitidine in patients with liver cirrhosis. Int J Clin Pharmacol Ther Toxicol 1984 Jun; 22(6): 329–32

    PubMed  CAS  Google Scholar 

  234. McFadyen ML, Folb PI, Miller R, et al. Pharmacokinetics of ranitidine in patients with chronic renal failure. Eur J Clin Pharmacol 1983; 25(3): 347–51

    Article  PubMed  CAS  Google Scholar 

  235. Garg DC, Baltodano N, Jallad NS, et al. Pharmacokinetics of ranitidine in patients with renal failure. J Clin Pharmacol 1986 Apr; 26(4): 286–91

    PubMed  CAS  Google Scholar 

  236. Suttle AB, Pollack GM, Brouwer KL. Use of a pharmacokinetic model incorporating discontinuous gastrointestinal absorption to examine the occurrence of double peaks in oral concentration-time profiles. Pharm Res 1992 Mar; 9(3): 350–6

    Article  PubMed  CAS  Google Scholar 

  237. Lauven PM, Stoeckel H, Schuttler J, et al. Prevention of fentanyl rebound by administration of cimetidine (author’s transl). Der Anaesthesist 1981 Sep; 30(9): 467–71

    PubMed  CAS  Google Scholar 

  238. Trausch B, Oertel R, Richter K, et al. Disposition and bioavailability of the beta 1-adrenoceptor antagonist talinolol in man. Biopharm Drug Dispos 1995 Jul; 16(5): 403–14

    Article  PubMed  CAS  Google Scholar 

  239. Gramatte T, Oertel R. Die resorption der substanz talinolol aus verschiedenen bereichen des dunndarmes [abstract]. Klin Pharmakoll Akt 1993; 4: 35

    Google Scholar 

  240. Gramatte T, Oertel R, Terhaag B, et al. Direct demonstration of small intestinal secretion and site-dependent absorption of the beta-blocker talinolol in humans. Clin Pharmacol Ther 1996 May; 59(5): 541–9

    Article  PubMed  CAS  Google Scholar 

  241. Okum GS, Hauser AC, Keykhah MM, et al. Sufentanil plasma concentrations following lower extremity tourniquet release. J Clin Anesth 1996 May; 8(3): 210–5

    Article  PubMed  CAS  Google Scholar 

  242. Hengstmann JH, Stoeckel H, Schuttler J. Infusion model for fentanyl based on pharmacokinetic analysis. Br J Anaesth 1980 Oct; 52(10): 1021–5

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Dr N.M. Davies has received grant support from the US National Institutes of Health, and Dr D.R. Brocks has received grant support from the Canadian Institutes of Health Research. No sources of funding were used to assist in the preparation of this review. The authors have no direct potential conflicts of interest related to the content of this review.

Dr J.A. Yáñez now works in Pharmacokinetics and Drug Metabolism at Alcon Laboratories, Inc. (Fort Worth, TX, USA).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Pharmacology and Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman, Washington, USA

    Neal M. Davies, Jody K. Takemoto & Jaime A. Yáñez

  2. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

    Dion R. Brocks

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  1. Neal M. Davies
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  2. Jody K. Takemoto
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  3. Dion R. Brocks
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  4. Jaime A. Yáñez
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Correspondence to Neal M. Davies.

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Davies, N.M., Takemoto, J.K., Brocks, D.R. et al. Multiple Peaking Phenomena in Pharmacokinetic Disposition. Clin Pharmacokinet 49, 351–377 (2010). https://doi.org/10.2165/11319320-000000000-00000

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