Summary
Theophylline is a bronchodilator used extensively in the management of obstructive pulmonary disease. Factors implicated in altered theophylline clearance include smoking, age, concomitant drug intake, liver disease and left ventricular heart failure. However, evidence now suggests that theophylline clearance may be altered by changes in severity of the pulmonary obstruction, hypoxia and variation in arterial pH.
The in vitro disposition of theophylline has been evaluated in isolated rat livers and mouse hepatocytes. In vivo studies have assessed the metabolism of theophylline under hypoxia in rats, rabbits and dogs. In isolated mouse hepatocytes and rat livers, low oxygen concentrations resulted in higher theophylline concentrations, a longer elimination half-life and a decrease in the production of the metabolite 1,3-dimethyl uric acid, suggesting impaired metabolism of theophylline. In rabbits, hypoxia, hypercapnia and respiratory acidosis decreased total body clearance and increased plasma theophylline concentrations. On the other hand, experiments involving dogs showed no significant changes in theophylline concentrations or pharmacokinetic parameters with hypoxia. At present, animal studies remain inconclusive. This can be attributed to the use of different animal models and variations in study methodology, including the extent and duration of hypoxia and acidaemia, concurrent acid-base disorders such as hypercapnia, as well as the severity of pulmonary obstruction.
Human studies assessing alterations in theophylline disposition secondary to the hypoxia present in pulmonary disease are few and include mostly case reports and observational studies. There is evidence suggesting decreased theophylline clearance and protein binding during acute illness and some consensus can be achieved using case reports and controlled studies. There is additional evidence that drug clearance decreases with age and that elderly patients may have a decreased theophylline clearance at baseline. However, the most obvious markers appear to be the severity of pulmonary disease and the rate of change in the patient’s condition. Caution should be exercised when administering theophylline to elderly patients with chronic obstructive pulmonary disease presenting with acute exacerbations of a concomitant respiratory illness, as these patients appear to be most likely to exhibit altered theophylline metabolism. Therefore, they would be at increased risk for toxicity should conventional dosages be used during an acute respiratory event.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Agnihotri SN, Clark RA, Cooper S, Iyun AO, Tucker GT. Chronic pulmonary disease and antipyrine disposition. British Journal of Clinical Pharmacology 5: 275–277, 1978
Arnold JD, Hill GN, Sansom LN. A comparison of the pharmacokinetics of theophylline in asthmatic children in the acute episode and in remission. European Journal of Clinical Pharmacology 20: 443–447, 1981
Au WYW, Dutt AK, DeSoyza N. Theophylline kinetics in chronic obstructive airway disease in the elderly. Clinical Pharmacology and Therapeutics 37: 472–478, 1985
Buss D, Leopold D, Smith AP, Routledge PA. Determinants of the plasma protein binding of theophylline in health. British Journal of Clinical Pharmacology 15: 399–405, 1983
Clozel JP, Saunier C, Royer-Morot M-J, Royer RJ, Sadoul P. Respiratory acidemia and theophylline pharmacokinetics in the awake dog. Chest 80: 631–633, 1981
Cumming JF. The effect of arterial oxygen tension on antipyrine half-time in plasma. Clinical Pharmacology and Therapeutics 19: 468–471, 1976
Cusack BJ, Crowley JJ, Mercer JD, Charan NB, Vestal RE. Theophylline clearance in patients with severe chronic obstructive pulmonary disease receiving supplemental oxygen and the effect of acute hypoxemia. American Review of Respiratory Diseases 133: 1110–1114, 1986
du Souich P, McLean AJ, Lalka D, Erill S, Gibaldi H. Pulmonary diseases and drug kinetics. Clinical Pharmacokinetics 3: 257–266, 1978
du Souich P, Hoen B, Saunier C, Hartemann D, Sautegeau A, et al. Theophylline disposition in patients with COLD with and without hypoxemia. Chest 95: 1028–1032, 1989
Edwards DJ, Zarowitz BJ, Slaughter RL. Theophylline. In Evans, et al. (Eds) Applied pharmacokinetics: principles of therapeutic drug monitoring, 3rd ed., Chapter 13, pp. 1–38, Applied Therapeutics, Spokane, WA, 1992
Gu L, Gonzalez FJ, Kalow W, Tang BK. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP 1A2 and CYP 2E1. Pharmacogenetics 2: 71–77, 1992
Gumucio JJ, Miller DL. Functional implications of liver cell heterogeneity. Gastroenterology 80: 393–403, 1981
Hendeles L, Bighley L, Richardson RH, Hepler CD, Carmichael J. Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intelligence and Clinical Pharmacy 11: 12–18, 1977
Jacobs MH, Senior RM. Theophylline toxicity due to impaired theophylline degradation. American Review of Respiratory Diseases 110: 342–345, 1974
Jenne JW, Chick TW, Miller BA, Strickland RD. Apparent theophylline half-life fluctuations during treatment of acute left ventricular failure. American Journal of Hospital Pharmacy 34: 408–409, 1977
Jones DP. Hypoxia and drug metabolism. Biochemistry and Pharmacology 30: 1019–1023, 1981
Jones DB, Mihaly GW, Smallwood RA, Webster LK, Morgan DJ, et al. Differential effects of hypoxia on the disposition of propranolol and sodium taurocholate by the isolated perfused rat liver. Hepatology 4: 461–466, 1984
Jones DP, Aw TY, Shan X. Drug metabolism and toxicity during hypoxia. Drug Metabolism Review 20: 247–260, 1989
Kishimoto K, Tanigawara Y, Okumura K, Ryohei H. Blood oxygen tension-related changes in theophylline clearance in experimental hypoxemia. Journal of Pharmacology and Experimental Therapeutics 248: 1237–1242, 1989
Laybourn C, Tonnensen P, Loft S, Bonne J, Dossing M. Pulmonary disease and antipyrine clearance. Clinical Pharmacology and Therapeutics 40: 415–419, 1986
Lee B, Benowitz NL, Jacob P. Cigarette abstinence, nicotine gum, and theophylline disposition. Annals of Internal Medicine 106: 553–555, 1987
Letarte L, du Souich P. Influence of hypercapnia and/or hypoxemia and metabolic acidosis on theophylline kinetics in the conscious rabbit. American Review of Respiratory Diseases 129: 762–766, 1984
Miller R, Oliver IF. The influence of oxygen tension on theophylline clearance in the isolated perfused liver. Journal of Pharmacy and Pharmacology 38: 236–238, 1986
Nakatsu K. Limitation of theophylline elimination by reduced oxygen availability in mouse hepatocytes and rat isolated livers. Canadian Journal of Physiology and Pharmacology 63: 903–907, 1985
Persson CGA, Andersson K-E. Respiratory and cardiovascular effects of 3-methylxanthine, a metabolite of theophylline. Acta Pharmacologica et Toxicologica 40: 529–536, 1977
Piafsky KM, Sitar DS, Rangno RE, Ogilvie RI. Theophylline kinetics in acute pulmonary oedema. Clinical Pharmacology and Therapeutics 21: 310–316, 1977
Powell JR, Vožeh S, Hopewell P, Costello J, Sheiner LB. Theophylline disposition in acutely ill hospitalized patients. American Review of Respiratory Diseases 118: 229–238, 1978
Resar RK, Walson PD, Fritz WL, Perry DF, Barbee RA. Kinetics of theophylline: variability and effect of arterial pH in chronic obstructive lung disease. Chest 76: 11–16, 1979
Robson RA, Matthews AP, Miners JO, McManus ME, Myer UA. Characterization of theophylline metabolism in human liver microsomes. British Journal of Clinical Pharmacology 24: 293–300, 1987
St-Pierre MV, Spino M, Isle AF, Teroso A, McLeod SM. Temporal variation in the disposition of theophylline and its metabolites. Clinical Pharmacology and Therapeutics 38: 89–95, 1985
Saunier C, du Souich P, Hartemann D, Sautageau A. Theophylline disposition during acute and chronic hypoxia in the conscious dog. Research Communications in Chemical Pathology and Pharmacology 57: 291–299, 1987
Shaw LM, Fields L, Mayock R. Factors influencing theophylline serum protein binding. Clinical Pharmacology and Therapeutics 32: 490–496, 1982
Tang-Liu DD-S, William RL, Riegelman S. Nonlinear theophylline elimination. Clinical Pharmacology and Therapeutics 31: 358–369, 1982
Vallner JJ, Speir WA, Kolbeck RC, Harrison GN, Bransome ED. Effect of pH on the binding of theophylline to serum proteins. American Review of Respiratory Diseases 120: 83–86, 1979
Vicuna N, McNay JL, Ludden TM, Schwertner H. Impaired theophylline clearance in patients with cor pulmonale. British Journal of Clinical Pharmacology 7: 33–37, 1979
Vožeh S, Powell JR, Riegelman S, Costello JF, Sheiner LB. Changes in theophylline clearance during acute illness. Journal of the American Medical Association 240: 1882–1884, 1978
Westerfield BT, Carder AJ, Light RW. The relationship between arterial blood gases and serum theophylline clearance in critically ill patients. American Review of Respiratory Diseases 124: 490–496, 1981
Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390, 1975
Zarowitz B, Sholm J, Eichenhorn MS, Popovich J. Alterations in theophylline protein binding in acutely ill patients with COPD. Chest 87: 766–769, 1985
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Richer, M., Lam, Y.W.F. Hypoxia, Arterial pH and Theophylline Disposition. Clin. Pharmacokinet. 25, 283–299 (1993). https://doi.org/10.2165/00003088-199325040-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199325040-00004