Lack of Effect of Aciclovir on Metabolism of Theophylline and Expression of Hepatic Cytochrome P450 1A2 in Rats
Biological and Pharmaceutical Bulletin
Theophylline is widely used in the treatment of patients with obstructive airway diseases. It is well known that theophylline has a narrow therapeutic range being a plasma concentration of 10-20 mg/ml 1,2) and is extensively metabolized in humans. 3, 4) Many articles have been published on the drug interactions of theophylline with other coadministered drugs mediated by cytochrome P450 (CYP) 1A2, which is the major metabolizing enzyme for theophylline. 5-12) For example, it is well known that
... s well known that histamine H 2 -antagonist cimetidine and quinolone antimicrobial agent enoxacin cause the risk of the development of serious side effects by inhibiting CYP1A2-mediated theophylline metabolism in the liver. 7, 9, 13, 14) The antivirus agent aciclovir, which has potent inhibitory activity against herpes simplex virus and varicella zoster virus,    is known to be mainly eliminated from the kidney. 18, 19) Drug interaction between aciclovir and concomitantly administered drugs, such as cimetidine, probenecid and mycophenolate that are primarily excreted into the urine has been reported.    However, there is an interesting clinical report indicating that total body clearance of theophylline is decreased by multiple oral administrations of aciclovir (800 mg five times daily for two consecutive days) in healthy volunteers, 23) although theophylline is extensively metabolized in the liver. They proposed that the mechanism responsible for the decreases in theophylline clearance by coadministration of aciclovir might be due to inhibition of CYP1A2-mediated theophylline metabolism. However, the effect of aciclovir on the activity and expression of CYP1A2 remains unclear. We have previously reported that rats are a useful animal model for predicting drug interaction between theophylline and other drugs in humans.       The aim of the present study was to investigate the effect of aciclovir on the pharmacokinetics and metabolism of theophylline, and on the activity and expression of hepatic CYP1A2 in rats. To further clarify whether aciclovir has an inhibitory effect against hepatic CYP1A2, we also investigated the effect of aciclovir on the pharmacokinetics of the xanthine derivative 1-methyl-3propylxanthine, which is almost completely metabolized by CYP1A2 in rats. 29, 30) MATERIALS AND METHODS Chemicals Theophylline, aciclovir, resorufin and 7ethoxyresorufin were purchased from Sigma Chemical Company (St. Louis, MO, U.S.A.). Aciclovir in the form of a commercial preparation for injection (Zovirax for IV infusion) was obtained from GlaxoSmithKline K.K. (Tokyo, Japan). Enprofylline, 1-methyl-3-propylxanthine and 1methyl-3-buthylxanthine were synthesized in our laboratory and were identical to those previously described. 29,31) Enprofylline and 1-methyl-3-buthylxanthine were used as internal standards for determination of concentrations of theophylline and 1-methyl-3-propylxanthine, respectively. Inulin was purchased from Nacalai Tesque (Kyoto, Japan). All other 562 There is an interesting clinical report indicating that aciclovir, which is mainly excreted into urine, decreases the systemic clearance of theophylline by inhibiting cytochrome P450 (CYP) 1A2-mediated metabolism. In this study, we investigated the effect of aciclovir on the metabolism of theophylline, and on the activity and expression of hepatic CYP1A2 in rats. Theophylline (10 mg/kg) was injected intravenously into rats treated with two different dosages of aciclovir. When theophylline was simultaneously administered with aciclovir (50 mg/kg), the systemic clearance of theophylline and metabolic clearance of its major metabolites, 1-methyluric acid and 1,3-dimethyluric acid, were unchanged. In place of theophylline, when 1-methyl-3-propylxanthine (2.5 mg/kg), which is almost metabolized by CYP1A2 in rats, was coadministered intravenously with aciclovir (50 mg/kg), the pharmacokinetics of 1-methyl-3-propylxanthine was also unchanged. When theophylline was administered to rats pretreated with repeated intraperitoneal injections of aciclovir (25 mg/kg twice daily for 3 d), no significant differences in the systemic clearance of theophylline and its metabolic clearance to 1-methyluric acid and 1,3-dimethyluric acid were observed between the control and aciclovir-treated rats. This dosage of aciclovir did not change the activity of 7-ethoxyresorufin O-dealkylation, which is represented as CYP1A2 activity. In Western blot analysis, no significant change in the protein levels of hepatic CYP1A2 was observed between the control and aciclovirtreated rats. The present study suggests that aciclovir has no effect on the pharmacokinetics and metabolism of theophylline and on the activity and expression of hepatic CYP1A2 in rats.