title: Increase in the systemic exposure of primary metabolites of Midazolam in rat arising from CYP inhibition or hepatic dysfunction.
abstract: The main purpose of this study is to demonstrate the possibility of increase in the systemic exposure of drug metabolites by CYP-inhibition or acute hepatitis. Midazolam (MDZ) was used as a model substrate of CYP3A and 1-aminobenzotriazole (ABT) was used as a CYP-inhibitor. After oral pretreatment with ABT, MDZ was intravenously injected to rats and the plasma profiles of MDZ and its primary metabolites, 1'-hydroxy MDZ and 4-hydroxy MDZ, were observed. In the ABT-pretreatment rats, plasma AUCs of both metabolites were much larger than those in control rats, demonstrating a higher systemic exposure of metabolites under CYP-inhibited condition. Furthermore, kinetic analysis revealed that the amount of both metabolites entered into the systemic circulation increased significantly (about 5-times). Increases in the systemic exposure of the primary metabolites of MDZ were also observed in the acute hepatitis rats induced by CCl4-pretreatment. As underlying mechanisms, it was speculated that ABT inhibited the subsequent metabolism of primary metabolites of MDZ in the hepatocytes and enhanced their release to the systemic circulation. In vitro study with rat liver microsomes supported this speculation. In conclusion, this study showed the complexity of PK profiles of drug metabolites, which might lead to new aspects on their safety issue.
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Nakanishi
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Minami
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Higashino
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kataoka
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Sanofi K.K., Tokyo, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan. Electronic address: shinji@pharm.setsunan.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006505:Hepatitis / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D008874:Midazolam
keywords: Acute hepatitis; CYP inhibition; Drug–drug interaction; Midazolam; Primary metabolites; Systemic exposure