Decreased elimination clearance of midazolam by doxorubicin through reductions in the metabolic activity of hepatic CYP3A in rats

• Published in: Xenobiotica 2015-10, Vol.45 (10), p.874-880
• Main Authors: Nagai, Katsuhito, Yoshida, Natsumi, Kiyama, Maho, Kasahara, Keita, Yamamura, Ayumi, Konishi, Hiroki
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Animals; CYP3A; Cytochrome P-450 CYP3A - metabolism; Doxorubicin - pharmacokinetics; Drug Interactions; drug-drug interaction; Enzymes - blood; Half-Life; hepatic metabolism; hepatotoxicity; Hydroxylation; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Metabolic Clearance Rate; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Midazolam - administration & dosage; Midazolam - pharmacokinetics; pharmacokinetics; Rats, Wistar
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2015.1027971

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 (t 1/2 ) of intravenously administered MDZ were significantly increased, and the total clearance (CL tot ) and the elimination rate constant at the terminal phase (k e ) were significantly decreased without significant changes in the volume of distribution at a steady state (Vd ss ). 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.