title: Inhibitory effect of antituberculosis drugs on human cytochrome P450-mediated activities.
abstract: The potential for drug-drug interactions mediated by the inhibition of cytochrome P-450 (CYP) were concerned during antituberculosis therapy. However, the information regarding human CYP inhibition by antituberculosis drugs is limited to isoniazid. In the current study, we examined the inhibitory effects of pyrazinamide and ethionamide, both of which are chemically related to isoniazid, on the CYP-mediated activities in human liver microsomes and compared them to that of isoniazid. No remarkable effects on any CYP activities were observed by pyrazinamide and ethionamide. In contrast, in addition to the reported inhibitory effect of isoniazid on CYP1A2, CYP2A6, CYP2C19, and CYP3A activities, our results newly showed its effect on CYP2C9 and CYP2E1 activities. Isoniazid showed potent direct inhibitory effect on S-warfarin 7-hydroxylation, while a preincubation step in the presence of NADPH was needed to inhibit chlorzoxazone 6-hydroxylation. Furthermore, irreversible inhibition of CYP2C19 activity by isoniazid was also observed in the dilution study. These results suggested that pyrazinamide and ethionamide did not seem to cause drug interactions mediated by the inhibition of CYP. In contrast, isoniazid might contribute to the severe drug interactions by a different inhibitory mechanism depending on each of the CYP isozymes, in addition to the reported observations.
authors.affiliation: Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan. yukin@med.showa-u.ac.jp
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Kurata
authors.forename: Eriko
authors.initials: E
authors.lastname: Sakurai
authors.forename: Hajime
authors.initials: H
authors.lastname: Yasuhara
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology
chemical_list: D000995:Antitubercular Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System