Lack of effect of aciclovir on metabolism of theophylline and expression of hepatic cytochrome P450 1A2 in rats.
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.
Nadai
Masayuki
M
Department of Pharmaceutics, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan.
Kato
Miki
M
Yasui
Kazumasa
K
Kimura
Masao
M
Zhao
Ying Lan
YL
Ueyama
Jun
J
Tsunekawa
Yoshimi
Y
Yoshizumi
Hideo
H
Hasegawa
Takaaki
T
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
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