1. We examined the effects of doxorubicin (DOX) on the expression level and metabolic activity of CYP3A in the liver as well as on the pharmacokinetics of midazolam (MDZ), a probe for CYP3A, in rats. Changes in the hepatic status of DOX-treated rats were confirmed. 2. Serum levels of the biomarkers of hepatic impairment were elevated by the DOX treatment, which was consistent with the results obtained from a histopathological evaluation of the liver. 3. No significant difference was observed in the expression of proteins for hepatic CYP3A1 and CYP3A2 between the DOX and control groups. The metabolic production of 1'-hydroxylated and 4'-hydroxylated MDZ by hepatic microsomes was significantly lower in DOX-treated rats than in control rats. 4. The area under the curve (AUC) and the half-life (t1/2) of intravenously administered MDZ were significantly increased, and the total clearance (CLtot) and the elimination rate constant at the terminal phase (ke) were significantly decreased without significant changes in the volume of distribution at a steady state (Vdss). 5. These results indicated that a DOX-induced depression in the metabolic activity, but not expression level of CYP3A contributed to a decrease in the elimination clearance of MDZ, and also that reduced CYP3A function may be associated with the hepatotoxicity of DOX.
Menthol is used widely as a constituent of functional foods and chemical drugs. The present study investigated changes in the pharmacokinetic behavior of intravenously administered midazolam (MDZ), a probe for CYP3A, when rats were treated with menthol. The study also examined which isoforms of CYP3A1 and 3A2 were menthol-inducible and contributed to the altered disposition of midazolam. Menthol was administered intraperitoneally to rats once daily for 3 days at a dose of 10 mg/kg, while the control rats received vehicle alone. The pharmacokinetic examination of i.v. administered midazolam revealed that serum midazolam concentrations at each sampling point were lower in the menthol-treated rats than in the control rats. Regarding the pharmacokinetic parameters of the menthol-treated group, the area under the curve (AUC) was decreased significantly and, correspondingly, the elimination rate constant at terminal phase (ke) was increased significantly without significant changes in the volume of distribution at steady state (Vdss). The metabolic production of the 1'-hydroxylated and 4'-hydroxylated forms of MDZ by hepatic microsomes was significantly greater in the menthol-treated rats than in the control rats. The expression levels of mRNA and protein for hepatic CYP3A2 were more than 2.5-fold higher than the control levels when the rats were treated with menthol, whereas no changes were observed in the expression levels of CYP3A1. These results indicate that menthol enhanced the elimination clearance of midazolam by inducing hepatic CYP3A2 and that careful attention should be paid when menthol is ingested in combination with drugs that act as substrates for CYP3A.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.