Temporal variation in the disposition of theophylline and its metabolites

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Abstract
The temporal aspects of theophylline disposition are of interest, as there are predictable time-dependent fluctuations in the pulmonary function of patients with asthma and theophylline serum concentrations may vary throughout a 24-h period. The extent to which there are significant temporal changes in theophylline kinetics and the relative contribution of distribution, metabolism and excretion to this phenomenon was studied. Eight healthy men received an i.v. dose (6 mg/kg) of theophylline at 800 h and 2000 h at 1-wk intervals. Serum and urine were analyzed for theophylline and its 3 major metabolites by HPLC [high performance liquid chromatography]. Distribution volumes and total body and nonrenal clearances showed no differences between morning and evening dosing. The elimination rate was 12% greater after morning dosing. Renal clearance was 24% greater after morning dosing and was accompanied by an increased excretion fraction of unchanged theophylline. Based on total urinary metabolite excretion and the metabolite serum AUCs [areas under concentration], there was no evidence of time-dependent variation in theophylline biotransformation. Although theophylline renal clearance is greater after morning dosing, it is only a small fraction of the overall drug elimination and does not change the total body clearance after morning or evening dosing.

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