title: Lack of effect of aciclovir on metabolism of theophylline and expression of hepatic cytochrome P450 1A2 in rats.
abstract: 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 aciclovir-treated 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.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nadai
authors.forename: Miki
authors.initials: M
authors.lastname: Kato
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yasui
authors.forename: Masao
authors.initials: M
authors.lastname: Kimura
authors.forename: Ying Lan
authors.initials: YL
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Ueyama
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tsunekawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Yoshizumi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017208:Rats, Wistar; D013806:Theophylline / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D014527:Uric Acid / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D014970:Xanthines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D014665:Vasodilator Agents; D014970:Xanthines; D014527:Uric Acid; C030530:1-methyluric acid; C058491:1-methyl-3-propylxanthine; D013806:Theophylline; C031274:1,3-dimethyluric acid; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D000212:Acyclovir