title: Difference in Mechanism-Based Inhibition of Cytochrome P450 3A4 and 3A5 by a Series of Fluoroquinolone Antibacterial Agents.
abstract: A series of fluoroquinolone antibacterial compounds were found to be irreversible (compounds 1-5) and quasi-irreversible (compounds 6-9) inhibitors of CYP3A4. The purpose of this study was to evaluate their mechanism-based inhibition (MBI) potency against CYP3A5. Compounds 1-5 were also irreversible inhibitors of CYP3A5, whereas compounds 6-9 showed neither irreversible nor quasi-irreversible inhibition of CYP3A5. Compounds 6 and 8 did not form a metabolite-intermediate complex with the heme of CYP3A5 during incubation. The structural analysis of the metabolites after incubation of compounds 1 and 6 with CYP3A5 revealed that their metabolites were identical to those produced by CYP3A4, including the precursors of which are speculated to account for the MBI of CYP3A4. The homology modeling of CYP3A5 suggests that four residues around the nitroso intermediate of compound 6 in the substrate-binding pocket of CYP3A4 correspond with the bulkier residues in CYP3A5-especially Phe210 in CYP3A5-which might contribute to the steric hindrance with the nitroso intermediate of compound 6. The substrate-binding pocket structure of CYP3A5 might prevent the nitroso intermediate from coordinate binding with the heme, thereby preventing quasi-irreversible inhibition. Our study may provide new insights into the observable differences between the inhibition of CYP3A4 and CYP3A5.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Company, Ltd., Tokyo, Japan (A.W., H.T., S.I., O.A.); Structural Biology Group, Biological Research Department, Daiichi Sankyo RD Novare Company, Ltd., Tokyo, Japan (T.K.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.) watanabe.akiko.mi@daiichisankyo.co.jp.
authors.forename: Akiko
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Company, Ltd., Tokyo, Japan (A.W., H.T., S.I., O.A.); Structural Biology Group, Biological Research Department, Daiichi Sankyo RD Novare Company, Ltd., Tokyo, Japan (T.K.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
authors.forename: Hideo
authors.initials: H
authors.lastname: Takakusa
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Company, Ltd., Tokyo, Japan (A.W., H.T., S.I., O.A.); Structural Biology Group, Biological Research Department, Daiichi Sankyo RD Novare Company, Ltd., Tokyo, Japan (T.K.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
authors.forename: Takako
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Company, Ltd., Tokyo, Japan (A.W., H.T., S.I., O.A.); Structural Biology Group, Biological Research Department, Daiichi Sankyo RD Novare Company, Ltd., Tokyo, Japan (T.K.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Inoue
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Company, Ltd., Tokyo, Japan (A.W., H.T., S.I., O.A.); Structural Biology Group, Biological Research Department, Daiichi Sankyo RD Novare Company, Ltd., Tokyo, Japan (T.K.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Company, Ltd., Tokyo, Japan (A.W., H.T., S.I., O.A.); Structural Biology Group, Biological Research Department, Daiichi Sankyo RD Novare Company, Ltd., Tokyo, Japan (T.K.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
authors.forename: Osamu
authors.initials: O
authors.lastname: Ando
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011994:Recombinant Proteins; D040681:Structural Homology, Protein; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D024841:Fluoroquinolones; D011994:Recombinant Proteins; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human