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Clinical Pharmacokinetics

, Volume 3, Issue 4, pp 267–293 | Cite as

Clinical Pharmacokinetics of Theophylline

  • R. I. Ogilvie
Article

Summary

Knowledge acquired of the kinetic disposition and effects of theophylline over the past 8 years has increased the clinical utility of the drug in the treatment of cardiorespiratory disorders. Although the anhydrous theophylline content varies greatly between products, there is similar excellent oral bioavailability. An average 96% (range 75 to 105%) of an uncoated theophylline tablet is absorbed, with peak concentrations occurring from 0.5 to 2.0h. Enteric coated and many sustained release preparations have poor bioavailability. Intravenous preparations of aminophylline contain from 75 to 85% theophylline by weight. Other routes of administration are not to be recommended.

In plasma, some 53 to 65% of theophylline is reversibly bound to protein. Premature neonates and adults with hepatic cirrhosis have reduced binding. The apparent volume of distribution in the steady state averages 0.5L/kg body weight regardless of sex, age (1 to 87 years), history of cigarette smoking, asthma, or acute pulmonary oedema. Premature neonates and adults with acidaemia, hepatic cirrhosis or obesity tend to have larger volumes of distribution for theophylline.

Theophylline is eliminated by biotransformation in the liver and urinary excretion of its metabolites. Approximately 7 to 13% is excreted unchanged in the urine by a first order process. One of the metabolites, 3-methylxanthine, which is pharmacologically active but less potent than theophylline, is eliminated by Michaelis-Menten kinetics. Removal of dietary methylxanthines can increase the rate of elimination of a single dose of theophylline. Dose dependent elimination kinetics has been suggested but not conclusively demonstrated.

The plasma theophylline concentration time curve after intravenous administration fits a 2 compartment open kinetic model with a rapid a distribution phase completed within 30 to 45 minutes after an intravenous dose. The β elimination phase t½β) is quite variable and in healthy adults ranges from 3 to 13h. As the apparent volume of distribution is little altered under most conditions, variations in theophylline elimination half-life reflect alterations in plasma theophylline clearance. The predominant factors which alter theophylline clearance are age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease.

The elimination of theophylline is markedly decreased in premature infants and increased in childhood. The rapid clearance in childhood decreases toward adult values in the late teens. Some authors believe old age per se decreases an individual’s capacity to eliminate theophylline. However, this may be a reflection of the inability of hepatic enzymes in the elderly to respond to factors in the diet or environment which usually stimulate theophylline clearance.

The elimination half-life of theophylline is prolonged in obese subjects and maintenance doses must be calculated from ideal body weight. Theophylline clearance can be decreased by a high carbohydrate-low protein diet, as well as the ingestion of other methylxanthines such as caffeine. In contrast, a low carbohydrate-high protein diet, especially charcoal broiled meat, may enhance theophylline clearance.

Theophylline clearance is markedly increased by tobacco or marihuana smoke. The rate of recovery from the stimulated state on cessation of smoking is unknown. Although there is some evidence that phenobarbitone treatment can slightly induce the hepatic metabolism of theophylline in vitro, the evidence in man for such an effect is inconclusive. The macrolide antibiotics, troleandomycin and erythromycin, are potent inhibitors of theophylline elimination.

There is no evidence that uncomplicated asthma or chronic bronchitis alters theophylline clearance but, as chronic obstructive lung disease ensues with complications such as pneumonia or cor pulmonale, theophylline clearance can be markedly impaired. The elimination of theophylline is also reduced by congestive heart failure or acute pulmonary oedema. The mechanism responsible for reduced theophylline clearance in patients with cardiorespiratory disease is unclear. Reduced hepatocellular function is apparently responsible for the most marked decrease in theophylline clearance in patients with hepatic cirrhosis. It is not clear if one or several biochemical tests of liver function will allow prediction of the degree of impairment of theophylline elimination in individual patients. Reduced theophylline clearance has been observed in febrile children with acute viral exanthems.

The bronchodilator effect of theophylline is related to plasma theophylline concentrations in the post-distribution period, indicating that the site of its bronchodilator activity is outside of the central kinetic compartment. Continuous improvement in forced expiratory volumes can be observed over the plasma theophylline concentration range of 5 to 20mg/L. These concentrations can reduce the frequency of asthmatic attacks, abolish exercise induced bronchospasm and increase the ventilatory response to hypoxaemia.

Plasma theophylline concentrations of 5 to 20mg/L can produce concentration related increases in forearm blood flow and reductions in cerebral blood flow. The mechanism responsible for the reduction in cerebral blood flow is not clear. Peripheral venous distensibility is maximally increased at 10mg/L. Cardiac output and heart rate are variably increased. Although myocardial oxygen consumption increases, there appears to be a greater increase in oxygen delivery by increased coronary blood flow, suggesting a direct reduction of coronary vascular resistance. Pulmonary vascular resistance is reduced with increased ventilation/perfusion abnormalities. Arterial oxygen tension may decrease in asthmatic patients even though airway obstruction is relieved.

Serious adverse effects are rare at plasma theophylline concentrations below 20mg/L. The most frequent adverse effects involve the gastrointestinal system (anorexia, nausea, vomiting, abdominal discomfort) and the nervous system (headache, nervousness, anxiety), which usually occur with concentrations over 15mg/L. Between 20 and 40mg/L, sinus tachycardia and atrial or ventricular arrhythmias occur with increasing frequency. Above 40mg/L, focal or generalised seizures, or cardiorespiratory arrest can occur.

For rapid attainment of therapeutic plasma theophylline concentrations, a loading dose of aminophylline 5.6mg/kg can be given over 20 minutes via a peripheral vein. Although this dose is relatively safe and almost universally applicable, caution must be exercised if the patient has received theophylline in the previous 12 to 24 hour period. Maintenance doses of theophylline for intravenous or oral use should be calculated based on ideal body weight and modified for the presence of factors which alter theophylline clearance.

Dose guidelines are approximations only and the wide variability in theophylline clearance between individuals and with disease makes their indiscriminant application hazardous. It is rational to begin with smaller than recommended doses and increase at intervals as tolerated until the recommended amounts are administered. In adult patients, one may limit theophylline doses to 16mg/kg daily unless a plasma theophylline concentration is obtained as a guide for further adjustment. With the proper resources, interpretive skills, and timing of plasma samples, theophylline concentrations can give the clinician sufficient information to prescribe ideal theophylline doses for an individual patient, provided the clinician searches for and recognises factors which alter theophylline clearance in that patient.

Keywords

Theophylline Clinical Pharmacokinetic Aminophylline Theophylline Concentration Theophylline Clearance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Adams, R.F.; Vandemark, L. and Schmidt, G.J.: More sensitive high-pressure liquid-chromatographic determination of theophylline in serum. Clinical Chemistry 22: 1903–1906 (1976).PubMedGoogle Scholar
  2. Aranda, J.V.; Sitar, D.S.; Parsons, W.D.; Loughnan, P.M. and Neims, A.H.: Pharmacokinetic aspects of theophylline in premature newborns. New England Journal of Medicine 295: 413–416 (1976).PubMedCrossRefGoogle Scholar
  3. Atuk, N.O.; Blaydes, M.C.; Westervelt, F.B. Jr. and Wood, J.E.: Effect of aminophylline on urinary excretion of epinephrine and norepinephrine in man. Circulation 35: 745–753 (1967).PubMedCrossRefGoogle Scholar
  4. Bailey, D.G.; Davis, H.L. and Johnson, G.E.: Improved theophylline serum analysis by an appropriate internal standard for gas chromatography. Journal of Chromatography 121: 263–268 (1976).PubMedCrossRefGoogle Scholar
  5. Banner, A.S.; Berman, E.; Sunderrajan, E.; Agarwal, M.K.; Kathan, R. and Addington, W.W.: Drug interferences with spectrophotometric assay of theophylline. New England Journal of Medicine 297: 170 (1977).PubMedGoogle Scholar
  6. Barnhart, J.L. and Combes, B.: Effect of theophylline on hepatic excretory function. American Journal of Physiology 227: 194–199 (1974).PubMedGoogle Scholar
  7. Bell, T. and Bigley, J.: Sustained-release theophylline therapy for chronic childhood asthma. In press (1978).Google Scholar
  8. Boroda, G; Miller, R.B.; Leslie, S.T.; Nicol, E.G. and Thomson, I.: Comparison of the bioavailability of aminophylline in a conventional base and in a continuous-release base. Journal of Clinical Pharmacology 13: 383–387 (1973).PubMedGoogle Scholar
  9. Brodie, B.B.; Axelrod, J. and Reichenthal, J.: Metabolism of theophylline (1,3-dimethylxanthine) in man. Journal of Biological Chemistry 193: 215–222 (1951).Google Scholar
  10. Buelow, K.B.; Larsson, H. and Leideman, T.: Plasma theophylline level and ventilatory function in chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate. European Journal of Clinical Pharmacology 8: 119–123 (1975).CrossRefGoogle Scholar
  11. Caldwell, J.; Lancaster, R.; Monks, T.J. and Smith, R.L.: The influence of dietary methylxanthines on the metabolism and pharmacokinetics of intravenously administered theophylline. British Journal of Clinical Pharmacology 4: 637P–638P (1977).PubMedCrossRefGoogle Scholar
  12. Chrzanowski, F.A.; Niebergall, P.J.; Nikelly, J.G.; Sugita, E.T. and Schnaare, R.L.: Gas chromatographic analysis of theophylline in human serum. Biochemical Medicine 11: 26–31 (1974).PubMedCrossRefGoogle Scholar
  13. Chrzanowski, F.; Niebergall, P.J.; Mayock, R.; Taubin, J. and Sugita, E.: Interference by butyl rubber stopper in GLC analysis for theophylline. Journal of Pharmaceutical Sciences 65: 735–736 (1976).PubMedCrossRefGoogle Scholar
  14. Chrzanowski, F.A.; Niebergall, P.J.; Mayock, R.L.; Taubin, J.M. and Sugita, E.T.: Kinetics of intravenous theophylline. Clinical Pharmacology and Therapeutics 22: 188–195 (1977).PubMedGoogle Scholar
  15. Chrzanowski, F.A. and Niebergall, P.J.: Kinetics of intravenous theophylline. Clinical Pharmacology and Therapeutics 22: 936 (1977).Google Scholar
  16. Cornbleet, P.J.; Schmitz, J. and Wolgin, A.: Drugs interfering with theophylline. New England Journal of Medicine 297: 669–670 (1977).Google Scholar
  17. Cornish, H.H. and Christman, A.A.: A study of the metabolism of theobromine, theophylline, and caffeine in man. Journal of Biological Chemistry 228: 315–323 (1957).PubMedGoogle Scholar
  18. Cummins, L.H.; Kozak, P.P. Jr. and Gillman, S.A.: Theophylline determinations. Annals of Allergy 37: 450–451 (1976).PubMedGoogle Scholar
  19. Danhof, M. and Breimer, D.D.: Therapeutic drug monitoring in saliva. Clinical Pharmacokinetics 3: 39–57 (1978).PubMedCrossRefGoogle Scholar
  20. Danish, M.; Gerbino, P.; Rohrbaugh, T. and Yaffe, S.: The effect of obesity on volume of distribution of theophylline. Submitted for publication (1978).Google Scholar
  21. Dyson, A.J. and Campbell, I.A.: Interaction between choline theophyllinate and salmefamol in patients with reversible airways obstruction. British Journal of Clinical Pharmacology 4: 677–682 (1977).CrossRefGoogle Scholar
  22. Ellis, E. and Eddy, E.D.: Anhydrous theophylline equivalence of commercial theophylline formulations. Journal of Allergy and Clinical Immunology 53: 116–119 (1974).PubMedCrossRefGoogle Scholar
  23. Ellis, E.F.; Koysooko, R. and Levy, G.: Pharmacokinetics of theophylline in children with asthma. Pediatrics 58: 542–547 (1976).PubMedGoogle Scholar
  24. Evenson, M.A. and Warren, B.: Serum theophylline analysis by high-pressure liquid chromatography. Clinical Chemistry 22: 851–855 (1976).PubMedGoogle Scholar
  25. Floyd, R.A. and Cohen, J.L.: Pharmacokinetics in drug therapy II: Applications of clinical pharmacokinetics in the assessment of theophylline therapy. Biopharmaceutics and Pharmacokinetics 34: 402–407 (1977).Google Scholar
  26. Franconi, L.C.; Hawk, G.L.; Sandmann, B.J. and Haney, W.G.: Determination of theophylline in plasma ultrafiltrate by reversed phase high pressure liquid chromatography. Annals of Chemistry 48: 372–375 (1976).CrossRefGoogle Scholar
  27. Frings, C.S.; Keefer, R.C. and Saloom, J.M.: A rapid and precise method for determining theophylline in serum. Clinical Toxicology 8: 553–561 (1975).PubMedCrossRefGoogle Scholar
  28. Gal, P.; Jusko, W.J.; Yurchak, A.M. and Franklin, B.A.: Theophylline disposition in obesity. Clinical Pharmacology and Therapeutics 23: 438–444 (1978).PubMedGoogle Scholar
  29. Giacoia, G.; Jusko, W.J.; Menke, J. and Koup, J.R.: Theophylline pharmacokinetics in premature infants with apnea. Journal of Pediatrics 89: 829–832 (1976).PubMedCrossRefGoogle Scholar
  30. Ginchansky, E. and Weinberger, M.: Relationship of theophylline clearance to oral dosage in children with chronic asthma. Pediatric Pharmacology and Therapeutics 91: 655–660 (1977).Google Scholar
  31. Gottstein, U. and Paulson, O.B.: The effect of intracarotid aminophylline infusion on the cerebral circulation. Stroke 3: 560–564 (1972).PubMedCrossRefGoogle Scholar
  32. Greene, J.; Danish, M.; Ragni, M.; Lecks, H. and Yaffe, S.: The effect of phenobarbital upon theophylline elimination kinetics in asthmatic children. Presented at the American Congress of Allergy and Immunology, New York City, 29 March (1977).Google Scholar
  33. Hambleton, G.; Weinberger, M.; Taylor, J.; Cavanaugh, M.; Ginchansky, E.; Godfrey, S.; Tooley, M.; Bell, T. and Greenberg, S.: Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. Lancet 1: 381–385 (1977).PubMedCrossRefGoogle Scholar
  34. Helander, S.; Lindell, S.E.; Lindholm, B.; Soederholm, B. and Westling, H.: The hemodynamic and respiratory effects of adrenaline and theophylline derivatives in bronchial asthma. Scandinavian Journal of Respiratory Diseases 48: 45–56 (1967).PubMedGoogle Scholar
  35. Hendeles, L.; Bighley, L.; Richardson, R.H.; Hepler, C.D. and Carmichael, J.: Frequent toxicity from I.V. aminophylline infusions in critically ill patients. Drug Intelligence and Clinical Pharmacy 11: 12–17 (1977a).Google Scholar
  36. Hendeles, L.; Weinberger, M. and Bighley, L.: Absolute bio-availability of oral theophylline. American Journal of Hospital Pharmacy 34: 525–527 (1977b).PubMedGoogle Scholar
  37. Hendeles, L.; Weinberger, M. and Johnson, G.: Monitoring serum theophylline levels. Clinical Pharmacokinetics 3: 294–312 (1978).PubMedCrossRefGoogle Scholar
  38. Hossie, R.D.; Sved, S.; McErlane, K. and McGilveray, I.J.: A comparison of two methods used to determine theophylline concentrations in plasma. Canadian Journal of Pharmaceutical Sciences 12: 39–41 (1977).Google Scholar
  39. Hunt, S.N.; Jusko, W.J. and Yurchak, A.M.: Effect of smoking on theophylline disposition. Clinical Pharmacology and Therapeutics 19: 546–551 (1976).PubMedGoogle Scholar
  40. Isaksson, B. and Linholm, B.: Blood plasma level of different theophylline derivatives following parenteral, oral and rectal administration. Acta Medica Scandinavica 171: 33–38 (1962).CrossRefGoogle Scholar
  41. Jacobs, M.H. and Senior, R.: Theophylline toxicity due to impaired theophylline degradation. American Review of Respiratory Disease 11: 342–345 (1974).Google Scholar
  42. Jacobs, M.H. and Senior, R.M.: Personal communication (1978).Google Scholar
  43. Jacobs, M.H.; Senior, R.M. and Kessler, G.: Clinical experience with theophylline. Relationships between dosage, serum concentration, and toxicity. Journal of the American Medical Association 235: 1983–1986 (1976).PubMedCrossRefGoogle Scholar
  44. Jatlow, P.: Ultraviolet spectrophotometry of theophylline in plasma in the presence of barbiturates. Clinical Chemistry 21: 1518–1520 (1975).PubMedGoogle Scholar
  45. Jenne, J.W.; Chick, T.W.; Miller, B.A. and Strickland, R.D.: Apparent theophylline half-life fluctuations during treatment of acute left ventricular failure. American Journal of Hospital Pharmacy 34: 408–409 (1977).PubMedGoogle Scholar
  46. Jenne, J.; Nagasawa, H.; McHugh, R.; MacDonald, F. and Wyse, E.: Decreased theophylline half-life in cigarette smokers. Life Sciences 17: 195–198 (1975).PubMedCrossRefGoogle Scholar
  47. Jenne, J.W.; Nagasawa, H.T. and Thompson, R.D.: Relationship of urinary metabolites of theophylline to serum theophylline levels. Clin. Pharm. Ther. 19: 375–381 (1976).Google Scholar
  48. Jenne, J.W.; Wyze, E.; Rood, B.S. and MacDonald, F.M.: Pharmacokinetics of theophylline. Application to adjustment of the clinical dose of aminophylline. Clinical Pharmacology and Therapeutics 13: 349–360 (1972).PubMedGoogle Scholar
  49. Jezek, V.; Ourednik, J.; Stepanek, J. and Boudik, F.: The effect of aminophylline on the respiration and pulmonary circulation. Clinical Science 38: 549–554 (1970).PubMedGoogle Scholar
  50. Johnson, G.F.; Dechtiaruk, W.A. and Solomon, H.M.: Gaschromatographic determination of theophylline in human serum and saliva. Clinical Chemistry 21: 144–147 (1975).PubMedGoogle Scholar
  51. Jusko, W.J.: Role of tobacco smoking in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 6: 7–39 (1978).PubMedGoogle Scholar
  52. Jusko, W.J.; Koup, J.R.; Vance, J.W.; Schentag, J.J. and Kuritzky, P.: Intravenous theophylline therapy: Nomogram guidelines. Annals of Internal Medicine 86: 400–404 (1977a).PubMedGoogle Scholar
  53. Jusko, W.J. and Poliszczuk, A.: High-pressure liquid chromatographic and spectrophotometry assays for theophylline in biological fluids. American Journal of Hospital Pharmacy 33: 1193–1196 (1976).PubMedGoogle Scholar
  54. Jusko, W.J.; Schentag, J.J.; Clark, J.H.; Gardner, M. and Yurchak, A.M.: Enhanced biotransformation of theophylline in marihuana and tobacco smokers. Submitted for publication (1978).Google Scholar
  55. Jusko, W.J.; Schentag, J.J. and Koup, J.R.: Pharmacokinetics of theophylline therapy. American Journal of Hospital Pharmacy 34: 332 (1977b).Google Scholar
  56. Kappas, A.; Anderson, K.E.; Conney, A.H. and Alvares, A.P.: Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clinical Pharmacology and Therapeutics 20: 643–653 (1977).Google Scholar
  57. Kappas, A.; Alvares, A.P.; Anderson, K.E.; Pantuck, E.J.; Pantuck, C.B.; Chang, R. and Conney, A.H.: Effect of charcoal-broiled beef on antipyrine and theophylline metabolism. Clinical Pharmacology and Therapeutics 23: 445–450 (1978).PubMedGoogle Scholar
  58. Kelly, J.G. and Shanks, R.G.: Comparison of plasma levels of theophyllinates after oral administration. British Journal of Clinical Pharmacology 3: 194–196 (1976).PubMedCrossRefGoogle Scholar
  59. Kordash, T.R.; Van Dellen, R.G. and McCall, J.T.: Theophylline concentrations in asthmatic patients after administration of aminophylline. Journal of the American Medical Association 288: 139–141 (1977).CrossRefGoogle Scholar
  60. Koup, J.R.; Schentag, J.J.; Vance, J.W.; Kuritzky, P.M.; Pyszczynski, D.R. and Jusko, W.J.: System for clinical pharmacokinetic monitoring of theophylline therapy. American Journal of Hospital Pharmacy 33: 949–956 (1976).PubMedGoogle Scholar
  61. Koysooko, R.; Ellis, E.F. and Levy, G.: Relationship between theophylline concentration in plasma and saliva of man. Clinical Pharmacology and Therapeutics 15: 454–460 (1974).PubMedGoogle Scholar
  62. Kozak, P.P.; Cummins, L.H. and Gillman, S.A.: Administration of erythromycin to patients on theophylline. Journal of Allergy and Clinical Immunology 16: 149–151 (1977).CrossRefGoogle Scholar
  63. Lakshminarayan, S.; Sahn, S.A. and Weil, J.V.: Effect of aminophylline on ventilatory responses in normal man. American Review of Respiratory Disease 117: 33–38 (1978).PubMedGoogle Scholar
  64. Landay, R.A.; Gonzales, M.A. and Taylor, J.C.: Effect of phenobarbital on theophylline disposition. Submitted for publication (1978).Google Scholar
  65. Larochelle, P. and Ogilvie, R.I.: Effect of drugs on effective vascular compliance in acute heart failure. Canadian Journal of Physiology and Pharmacology 53: 504–507 (1975).PubMedCrossRefGoogle Scholar
  66. Lawyer, C.H.; Keppel, J. and Bardana, E.J.: Theophylline in liver disease. New England Journal of Medicine 297: 1122–1123 (1977).CrossRefGoogle Scholar
  67. Least, C.J. Jr.; Johnson, G.F. and Solomon, H.M.: Gas-chromatographic micro-scale procedure for theophylline, with use of a nitrogen-sensitive detector. Clinical Chemistry 22: 765–768 (1976).PubMedGoogle Scholar
  68. Leung, P.; Kalisker, A. and Bell, T.D.: Variation in theophylline clearance rate with time in chronic childhood asthma. Journal of Allergy and Clinical Immunology 59: 440–444 (1977).PubMedCrossRefGoogle Scholar
  69. Levy, G. and Koysooko, R.: Pharmacokinetic analysis of the effect of theophylline on pulmonary function in asthmatic children. Journal of Pediatrics 86: 789–793 (1975).PubMedCrossRefGoogle Scholar
  70. Levy, G. and Koysooko, R.: Renal clearance of theophylline in man. Journal of Clinical Pharmacology 16: 329–332 (1976).PubMedGoogle Scholar
  71. Levy, G.; Gibson, T.P.; Whitman, W. and Procknal, J.: Hemodialysis clearance of theophylline. Journal of the American Medical Association 237: 1466–1467 (1977).PubMedCrossRefGoogle Scholar
  72. Lillehei, J.P.: Aminophylline. Oral vs rectal administration. Journal of the American Medical Association 205: 118–533 (1968).Google Scholar
  73. Lohmann, S.M. and Miech, R.P.: Theophylline metabolism by the rat liver microsomal system. Journal of Pharmacology and Experimental Therapeutics 196: 213–225 (1976).PubMedGoogle Scholar
  74. Loren, M.; Miklich, D.R.; Chai, H. and Barwise, G.: Aminophylline bioavailability and the across-time stability of plasma theophylline levels. Journal of Pediatrics 90: 473–476 (1977).PubMedCrossRefGoogle Scholar
  75. Loughnan, P.M.; Sitar, D.S.; Ogilvie, R.I.; Eisen, A.; Fox, Z. and Neims, A.H.: Pharmacokinetic analysis of the disposition of intravenous theophylline in young children. Journal of Pediatrics 88: 874–879 (1976).PubMedCrossRefGoogle Scholar
  76. Magnussen, I. and Høedt-Rasmussen, K.: The effect of intra-arterial administered aminophylline on cerebral hemodynamics in man. Acta Neurologica Scandinavica 55: 131–136 (1977).PubMedCrossRefGoogle Scholar
  77. Mangione, A.; Jusko, W.J.; Imhoff, T.E. and Lee, R.V.: Theophylline in liver disease. New England Journal of Medicine 297: 1123 (1977).Google Scholar
  78. Mangione, A.; Imhoff, T.E.; Lee, R.V.; Shum, L.Y. and Jusko, W.J.: Pharmacokinetics of theophylline in liver disease. Chest. In press (1978).Google Scholar
  79. Manion, C.V.; Shoeman, D.W. and Azarnoff, D.L.: High-pressure chromatographic assay of theophylline in biological fluids. Journal of Chromatography 101: 169–174 (1974).PubMedCrossRefGoogle Scholar
  80. Marcus, M.L.; Skelton, C.L.; Grauer, L.E. and Epstein, S.E.: Effects of theophylline on myocardial mechanics. American Journal of Physiology 222: 1361–1365 (1972).PubMedGoogle Scholar
  81. Marlin, G.E.; Hartnett, B.J.S. and Berend, N.: Assessment of combined oral theophylline and inhaled β-adrenoceptor agonist bronchodilator therapy. British Journal of Clinical Pharmacology 5: 45–50 (1978).PubMedCrossRefGoogle Scholar
  82. Maselli, R.; Casal, G.L. and Ellis, E.F.: Pharmacologic effects of intravenously administered aminophylline in asthmatic children. Journal of Pediatrics 76: 777–782 (1970).PubMedCrossRefGoogle Scholar
  83. Matheson, L.E. Jr.; Bighley, L. and Hendeles, L.: Drug interference with the Schack and Waxier plasma theophylline assay. American Journal of Hospital Pharmacy 34: 496–499 (1977).PubMedGoogle Scholar
  84. Mitenko, P.A. and Ogilvie, R.I.: Rapidly achieved plasma concentration plateaus, with observations on theophylline kinetics. Clinical Pharmacology and Therapeutics 13: 329–335 (1972).PubMedGoogle Scholar
  85. Mitenko, P.A. and Ogilvie, R.I.: Pharmacokinetics of intravenous theophylline. Clinical Pharmacology and Therapeutics 14: 509–513 (1973a).PubMedGoogle Scholar
  86. Mitenko, P.A. and Ogilvie, R.I.: Rational intravenous doses of theophylline. New England of Medicine 289: 600–603 (1973b).CrossRefGoogle Scholar
  87. Mitenko, P.A. and Ogilvie, R.I.: Bioavailability and efficacy of a sustained-release theophylline tablet. Clinical Pharmacology and Therapeutics 16: 720–726 (1974).PubMedGoogle Scholar
  88. Murphy, G.W.; Schreiner, B.F. Jr. and Yu, P.N.: Effects of aminophylline on the pulmonary circulation and left ventricular performance in patients with valvular heart disease. Circulation 37: 361–369 (1968).PubMedCrossRefGoogle Scholar
  89. Neese, A.L. and Soyka, L.F.: Development of a radioimmunoassay for theophylline application to studies in premature infants. Clinical Pharmacology and Therapeutics 21: 633–641 (1977).PubMedGoogle Scholar
  90. Nicholson, D.P. and Chick, T.W.: A re-evaluation of parenteral aminophylline. American Review of Respiratory Disease 108: 241–247 (1973).PubMedGoogle Scholar
  91. Nies, A.S.; Shand, D.G. and Wilkinson, G.R.: Altered hepatic blood flow and drug disposition. Clinical Pharmacokinetics 1: 135–155 (1976).PubMedCrossRefGoogle Scholar
  92. Oei, H.H.; Hale, T.H.; Gandhi, S.S.; Pilla, T.J. and Wegria, R.: Effect of aminophylline on coronary circulation and cardiac metabolism. Archives Internal Pharmacodynamics 229: 95–104 (1977).Google Scholar
  93. Ogilvie, R.I.: Smoking and theophylline dose schedules. Annals of Internal Medicine 88: 263–264 (1978).PubMedGoogle Scholar
  94. Ogilvie, R.I.; Fernandez, P.G. and Winsberg, F.: Cardiovascular response to increasing theophylline concentrations. European Journal of Clinical Pharmacology 12: 409–414 (1977).PubMedCrossRefGoogle Scholar
  95. Ogilvie, R.I.; Sitar, D.S. and Rangno, R.E.: Theophylline in liver disease. New England Journal of Medicine 297: 1123–1124 (1977).Google Scholar
  96. Parker, J.O.; Ashekian, P.B.; Di Giorgi, S. and West, R.O.: Hemodynamic effects of aminophylline in chronic obstructive pulmonary disease. Circulation 35: 362–365 (1967).CrossRefGoogle Scholar
  97. Parker, J.O.; Kelly, G. and West, R.O.: Hemodynamic effects of aminophylline in heart failure. American Journal of Cardiology 17: 232–239 (1966).PubMedCrossRefGoogle Scholar
  98. Parker, J.O.; Kelkar, K. and West, R.O.: Hemodynamic effects of aminophylline in cor pulmonale. Circulation 33: 17–25 (1966).PubMedCrossRefGoogle Scholar
  99. Peng, G.W.; Smith, V.; Peng, A. and Chiou, W.L.: A rapid and sensitive method for determination of theophylline in plasma and saliva by high pressure liquid chromatography. Research Communications in Chemical Pathology and Pharmacology 15: 341–350 (1976).PubMedGoogle Scholar
  100. Perrier, D. and Lear, E.: Gas-chromatographic quantitation of theophylline in small volumes of plasma. Clinical Chemistry 22: 898–900 (1976).PubMedGoogle Scholar
  101. Persson, C.G.A. and Andersson, K.E.: Respiratory and cardiovascular effects of 3-methylxanthine, a metabolite of theophylline. Acta Pharmacologica and Toxicologica 40: 529–536 (1977).Google Scholar
  102. Pfeifer, H.J. and Greenblatt, D.J.: Clinical toxicity of theophylline in relation to cigarette smoking: A report from the Boston Collaborative Drug Surveillance Program. Chest 73: 455–459 (1978).PubMedCrossRefGoogle Scholar
  103. Pfeifer, H.J.; Greenblatt, D.J. and Friedman, P.: Effect of antibiotics on theophylline kinetics in humans. Clinical Pharmacology and Therapeutics (abstract) 23: 124–125 (1978).Google Scholar
  104. Piafsky, K.M. and Ogilvie, R.I.: Drug therapy. Dosage of theophylline in bronchial asthma. New England Journal of Medicine 292: 1218–1222 (1975).PubMedCrossRefGoogle Scholar
  105. Piafsky, K.M.; Sitar, D.S.; Rangno, R.E. and Ogilvie, R.I.: Theophylline kinetics in acute pulmonary edema. Clinical Pharmacology and Therapeutics 21: 310–316 (1977a).PubMedGoogle Scholar
  106. Piafsky, K.M.; Sitar, D.S.; Rangno, R.E. and Ogilvie, R.I.: Theophylline disposition in patients with hepatic cirrhosis. New England Journal of Medicine 296: 1495–1497 (1977b).PubMedCrossRefGoogle Scholar
  107. Piafsky, K.M.; Sitar, D.S. and Ogilvie, R.I.: Effect of phenobarbital on the disposition of intravenous theophylline. Clinical Pharmacology and Therapeutics 22: 336–339 (1977c).PubMedGoogle Scholar
  108. Pollock, J.; Kiechel, F. and Cooper, D.; Relationship of serum theophylline concentration to inhibition of exercise-induced bronchospasm and comparison with chromolyn. Pediatrics. In press (1978).Google Scholar
  109. Powell, R.J.; Thiercelin, J.F.; Vozeh, S.; Sansom, L. and Riegelman, S.: The influence of cigarette smoking and sex on theophylline disposition. American Review of Respiratory Disease 116: 17–23 (1977).PubMedGoogle Scholar
  110. Powell, J.R.; Vozeh, S.; Hopewell, P.; Costello, J.; Sheiner, L.B. and Riegelman, S.: Theophylline disposition in acutely ill hospitalized patients. The effect of smoking, heart failure, severe airways obstruction and pneumonia. American Review of Respiratory Diseases. In press (1978).Google Scholar
  111. Quimby, C.W. Jr.; Aviado, D.M. Jr. and Schmidt, C.F.: The effects of aminophylline and other xanthines on the pulmonary circulation. Journal of Pharmacology and Experimental Therapeutics 122: 396–405 (1958).PubMedGoogle Scholar
  112. Rangsithienchai, P. and Newcomb, R.W.: Aminophylline therapy in children: Guidelines for dosage. Journal of Pediatrics 91: 325–330 (1977).PubMedCrossRefGoogle Scholar
  113. Rees, H.A.; Borthwick, R.C.; Millar, J.S. and Donald, K.W.: Aminophylline in bronchial asthma. Lancet 2: 1167–1169 (1967).PubMedCrossRefGoogle Scholar
  114. Rees, H.A.; MacDonald, H.R.; Borthwick, R.G.; Muir, A.L. and Donald, K.W.: The circulatory effects of aminophylline in man. Clinical Science 36: 359–369 (1969).PubMedGoogle Scholar
  115. Resai, R.; Walson, P.; Fritz, B. and Barbee, R.: Effect of arterial pH on intravenous theophylline loading in chronic obstructive pulmonary disease. American Review of Respiratory Diseases 115: 155 (1977).Google Scholar
  116. Resar, R.K.; Walson, P.D.; Fritz, W.; Perry, D.F. and Barbee, R.A.: Theophylline kinetics, variability, and effect of arterial pH in chronic obstructive lung disease. Submitted for publication (1978).Google Scholar
  117. Rutherford, J.D.; Vatner, S.F. and Braunwald, E.: Aminophylline induced alpha adrenergic coronary constriction and beta adrenergic inotropic stimulation in conscious dogs. Clinical Research 26: 485a (1978).Google Scholar
  118. Salem, H. and Jackson, R.H.: Oral theophylline preparations — a review of their clinical efficacy in the treatment of bronchial asthma. Annals of Allergy 32: 189–199 (1974).PubMedGoogle Scholar
  119. Schack, J.A. and Waxier, S.H.: An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues. Journal of Pharmacology and Experimental Therapeutics 97: 283–291 (1949).PubMedGoogle Scholar
  120. Schueren, K.P.; Huettemann, U.; Ramdohr, B. and Lohmann, F.W.: Lungenkreislauf und contractile Funktion des rechten Ventrikels bei chronischem Cor Pulmonale: Vergleichende Untersuchungen uber den Einflus von minophyllin und heptaminol. Klinische Wochenschrift 50: 101–111 (1972).CrossRefGoogle Scholar
  121. Segal, M.S.; Levinson, L.; Bresnick, E. and Beakey, J.F.: Evaluation of therapeutic substances employed for the relief of bronchospasm. VI. aminophylline. Journal of Clinical Investigation 28: 1190–1195 (1949).CrossRefGoogle Scholar
  122. Shah, V.P. and Reigelman, S.: GLC determination of theophylline in biological fluids. Journal of Pharmaceutical Sciences 63: 1283–1285 (1974).PubMedCrossRefGoogle Scholar
  123. Shannon, D.C.; Gotay, F. and Stein, I.M.: Prevention of apnea and bradycardia in low birthweight infants. Pediatrics 55: 589–594 (1975).PubMedGoogle Scholar
  124. Sheehan, M. and Haythorn, P.: Rapid gas chromatographic determination of underivatized theophylline in whole blood. Journal of Chromatography 117: 393–398 (1976).CrossRefGoogle Scholar
  125. Sigurd, B. and Olesen, K.H.: The supra-additive natriuretic effect addition of theophylline ethylenediamine and bumetanide in congestive heart failure. American Heart Journal 94: 168–174 (1977).PubMedCrossRefGoogle Scholar
  126. Sitar, S.; Piafsky, K.M.; Rangno, R.E. and Ogilvie, R.I.: Plasma theophylline concentrations measured by high-pressure liquid chromatography. Clinical Chemistry 21: 1774–1776 (1975).PubMedGoogle Scholar
  127. Sitar, D.S.; Nadeau, J.H. and Ruedy, J.R.: Comparative bioavailability of two oral dosage forms of oxtriphylline. Current Therapeutic Research 21: 233–239 (1977).PubMedGoogle Scholar
  128. Skinhøj, E. and Paulson, O.B.: The mechanism of action of aminophylline upon cerebral vascular disorders. Acta Neurologica Scandinavica 46: 129–140 (1970).PubMedCrossRefGoogle Scholar
  129. Soldin, S.J. and Hill, J.G.: A rapid micromethod for measuring theophylline in serum by reverse-phase high-performance liquid chromatography. Clinical Biochemistry 10: 74–77 (1977).PubMedCrossRefGoogle Scholar
  130. Spangler, D.L.; Kalof, D.D.; Bloom, F.L. and Wittig, H.J.: Theophylline bioavailability following oral administration of six sustained-release preparations. Annals of Allergy 40: 6–11 (1978).PubMedGoogle Scholar
  131. Stewart, B.N. and Block, A.J.: A trial of aerosolized theophylline in relieving bronchospasm. Chest 69: 717–721 (1976).CrossRefGoogle Scholar
  132. Sved, S.; Hossie, R.D. and McGilveray, I.J.: The human metabolism of caffeine to theophylline. Research Communications in Chemical Pathology and Pharmacology 13: 185–192 (1976).PubMedGoogle Scholar
  133. Tal, A. and Miklich, D.R.: The effect of induced emotions as 1 second forced expiration volume (FEV,) in asthmatic children. Journal of Allergy and Clinical Immunology 55: 125 (1975).Google Scholar
  134. Thompson, R.D.; Nagasawa, H.T. and Jenne, J.W.: Determination of theophylline and its metabolites in human urine and serum by high-pressure liquid chromatography. Journal of Laboratory and Clinical Medicine 84: 584–593 (1974).PubMedGoogle Scholar
  135. Truitt, E.B. Jr.; McKusick, V.A. and Krantz, J.C.: Theophylline blood levels after oral, rectal, and intravenous administration, and correlation with diuretic action. Journal of Pharmacology and Experimental Therapeutics 100: 309–315 (1950).PubMedGoogle Scholar
  136. Ueda, H.; Nakanishi, A.; Shiba, M.; Ito, I.; Tsuyuki, H.; Yasuda, H.; Koide, T.; Sugishita, Y.; Uchida, Y. and Machida, K.: The acute effect of aminophylline on left ventricular function in patients with heart failure. Clinical studies on the cardiac performance by means of left heart catheterization. Japanese Heart Journal 8: 121–131 (1967).PubMedCrossRefGoogle Scholar
  137. Vasiliades, J. and Turner, T.: A modified ultraviolet spectrophotometric method for the determination of theophylline in serum in the presence of barbiturates. Clinica Chimica Acta 69: 491–495 (1976).CrossRefGoogle Scholar
  138. Vaucher, Y.; Lightner, E.S. and Walson, P.D.: Theophylline poisoning. Journal of Pediatrics 90: 827–830 (1977).PubMedCrossRefGoogle Scholar
  139. Vozeh, S.; Upton, R.A.; Riegelman, S. and Scheiner, L.B.: Bronchodilator Therapy, Letter to the Editor. New England Journal of Medicine 298: 220 (1978).Google Scholar
  140. Walson, P.D.; Strunk, R.C. and Taussig, L.M.: Intrapatient variability in theophylline kinetics. Journal of Pediatrics 91: 321–324 (1977).PubMedCrossRefGoogle Scholar
  141. Weinberger, M.: Theophylline for treatment of asthma. Journal of Pediatrics 92: 1–7 (1978).PubMedCrossRefGoogle Scholar
  142. Weinberger, M. and Bronsky, E. with the assistance of Bensch, G.W.; Bock, G.N. and Yecies, J.J.: Interaction of ephedrine and theophylline. Clinical Pharmacology and Therapeutics 17: 585–592 (1975).PubMedGoogle Scholar
  143. Weinberger, M.M. and Bronsky, E.A.: Evaluation of oral bronchodilator therapy in asthmatic children. Journal of Pediatrics 84: 421–427 (1974).PubMedCrossRefGoogle Scholar
  144. Weinberger, M. and Chidsey, C.: Rapid analysis for theophylline in serum by use of high-pressure cation-exchange chromatography. Clinical Chemistry 21: 834–837 (1975).PubMedGoogle Scholar
  145. Weinberger, M. and Ginchansky, E.: Theophyllinization of the child with chronic asthma; in Gouveia, Tognoni and van der Klein (Eds) Clinical Pharmacy and Clinical Pharmacology, pp. 319–328 (Elsevier North-Holland, Amsterdam 1976).Google Scholar
  146. Weinberger, M. and Ginchansky, E.: Dose-dependent kinetics of theophylline disposition in asthmatic children. Journal of Pediatrics 5: 820–824 (1977).Google Scholar
  147. Weinberger, M.; Hudgel, D.; Spector, S. and Chidsey, C.: Inhibition of theophylline clearance by troleandomycin. Journal of Allergy and Clinical Immunology 59: 228–231 (1977).PubMedCrossRefGoogle Scholar
  148. Weinberger, M.; Matthay, R.A.; Ginchansky, E.J., Chidsey, C.A. and Petty, T.L.: Intravenous aminophylline dosage. Journal of the American Medical Association 235: 2110–2113 (1976).PubMedCrossRefGoogle Scholar
  149. Welling, P.G.; Domoradzki, J.; Sims, J.A. and Reed, C.E.: Influence of formulation on bioavailability of theophylline. Journal of Clinical Pharmacology 16: 43–50 (1976).PubMedGoogle Scholar
  150. Welling, P.G.; Lyons, L.L.; Craig, W.A. and Trochta, G.A.: Influence of diet and fluid on bioavailability of theophylline. Clinical Pharmacology and Therapeutics 17: 475–480 (1975).PubMedGoogle Scholar
  151. Wilkinson, G.R. and Shand, D.G.: A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390 (1975).PubMedGoogle Scholar
  152. Williams, J.F. and Szentivanyi, A.: Implications of hepatic drug-metabolizing activity in the therapy of bronchial asthma. Journal of Allergy and Clinical Immunology 55: 125 (1975).Google Scholar
  153. Wolfe, J.D.; Tashkin, D.P.; Calvarese, B. and Simmons, M.: Bronchodilator effects of terbutaline and aminophylline alone and in combination in asthmatic patients. New England Journal of Medicine 298: 363–367 (1978).PubMedCrossRefGoogle Scholar
  154. Wyatt, R.; Weinberger, M. and Hendeles, L.: Oral theophylline dosage for the management of chronic asthma. Journal of Pediatrics 92: 125–130 (1978).PubMedCrossRefGoogle Scholar
  155. Yeh, T.F. and Pildes, R.S.: Transplacental aminophylline toxicity in a neonate. Lancet 1: 910 (1977).PubMedCrossRefGoogle Scholar
  156. Yurchak, A.M. and Jusko, W.J.: Theophylline secretion into breast milk. Pediatrics 57: 518–520 (1976).PubMedGoogle Scholar
  157. Zaske, D.E.; Miller, K.W.; Strem, E.L.; Austrian, S. and Johnson, P.B.: Oral aminophylline therapy. Journal of the American Medical Association 237: 1453–1455 (1977).PubMedCrossRefGoogle Scholar
  158. Zwillich, C.; Sutton, F.D. Jr.; Neff, T.A.; Cohen, W.M.; Matthey, R.A. and Weinberger, M.M.: Theophylline-induced seizures in adults. Correlation with serum concentrations. Annals of Internal Medicine 82: 784–787 (1975).PubMedGoogle Scholar

Copyright information

© ADIS Press 1978

Authors and Affiliations

  • R. I. Ogilvie
    • 1
    • 2
  1. 1.Clinical Pharmacology DivisionMontreal General HospitalMontrealCanada
  2. 2.Departments of Medicine, Pharmacology and TherapeuticsMcGill UniversityMontrealCanada

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