Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates, and ethanol.

Pharmacokinetic, pathophysiologic, and historic data were systematically collected while monitoring theophylline therapy in adult pulmonary patients and from special studies in pediatric patients, normal volunteers, and patients with other diseases. Total body clearances (ClT) were estimated by nonlinear computer analysis after infusion dosage or from area under the curve data following single oral or intravenous theophylline doses. The ClT values, primarily reflecting the theophylline biotransformation rate, averaged 58 (±30) ml/hr/kg and ranged from 4 to 143 ml/hr/kg. Factors examined for their effect on theophylline ClT included age; sex; liver disease; congestive heart failure; obesity; renal function; history of drug, tobacco, marijuana, caffeine, or alcohol use; and pregnancy. The NYBAID (automatic interaction detector) computer program for analysis of variance was employed to determine the order, priority, and combinations of independent variables correlating with ClT. The major factors that affected theophylline ClT in this population included age, liver disease, smoking status, and congestive heart failure. Age showed strong correlation (r = −0.49) with ClT. Much additional variability was accounted for in specific subgroups. For example, young adult (20-40 years) marijuana users exhibited highest ClT vales (83 ± 29 ml/hr/kg) while older patients (>40 years) with liver disease had the lowest metabolism rates (22 ± 10 ml/hr/kg). In particular subject types, sex (in teenagers), oral contraceptives (in smokers), obesity (in young nonsmokers), and barbiturates also affected theophylline disposition. In contrast, several common factors such as chronic theophylline, chronic corticosteroids, caffeine, sex (in adults), and pregnancy did not alter theophylline ClT.- This unique clinical pharmacokinetic monitoring and statistical approach to drug clearance characterization in patients permits identification of criteria in a format that may be useful for the prediction of drug disposition rates and dosage regimens.