title: Investigation of drug-drug interactions caused by human pregnane X receptor-mediated induction of CYP3A4 and CYP2C subfamilies in chimeric mice with a humanized liver.
abstract: The induction of cytochrome P450 (P450) enzymes is one of the risk factors for drug-drug interactions (DDIs). To date, the human pregnane X receptor (PXR)-mediated CYP3A4 induction has been well studied. In addition to CYP3A4, the expression of CYP2C subfamily is also regulated by PXR, and the DDIs caused by the induction of CYP2C enzymes have been reported to have a major clinical impact. The purpose of the present study was to investigate whether chimeric mice with a humanized liver (PXB mice) can be a suitable animal model for investigating the PXR-mediated induction of CYP2C subfamily, together with CYP3A4. We evaluated the inductive effect of rifampicin (RIF), a typical human PXR ligand, on the plasma exposure to the four P450 substrate drugs (triazolam/CYP3A4, pioglitazone/CYP2C8, (S)-warfarin/CYP2C9, and (S)-(-)-mephenytoin/CYP2C19) by cassette dosing in PXB mice. The induction of several drug-metabolizing enzymes and transporters in the liver was also examined by measuring the enzyme activity and mRNA expression levels. Significant reductions in the exposure to triazolam, pioglitazone, and (S)-(-)-mephenytoin, but not to (S)-warfarin, were observed. In contrast to the in vivo results, all the four P450 isoforms, including CYP2C9, were elevated by RIF treatment. The discrepancy in the (S)-warfarin results between in vivo and in vitro studies may be attributed to the relatively small contribution of CYP2C9 to (S)-warfarin elimination in the PXB mice used in this study. In summary, PXB mice are a useful animal model to examine DDIs caused by PXR-mediated induction of CYP2C and CYP3A4.
authors: Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan. maki.hasegawa@kyowa-kirin.co.jp
authors: Maki
authors: M
authors: Hasegawa
authors: Harunobu
authors: H
authors: Tahara
authors: Ryo
authors: R
authors: Inoue
authors: Masakazu
authors: M
authors: Kakuni
authors: Chise
authors: C
authors: Tateno
authors: Junko
authors: J
authors: Ushiki
mesh_terms: D000818:Animals; D001692:Biological Transport; D001711:Biotransformation; D002678:Chimera; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008617:Mephenytoin / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D023421:Models, Animal; D000077205:Pioglitazone; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology; D045162:Thiazolidinediones / Q000378:metabolism / Q000493:pharmacokinetics; D014229:Triazolam / Q000378:metabolism / Q000493:pharmacokinetics; D014859:Warfarin / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D045162:Thiazolidinediones; C400322:cytochrome P-450 CYP2C subfamily; D014229:Triazolam; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; D008617:Mephenytoin; D012293:Rifampin; D000077205:Pioglitazone