title: Coordinated roles of pregnane X receptor and constitutive androstane receptor in autoinduction of voriconazole metabolism in mice.
abstract: The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the species-specific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr- and Car-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed in Pxr-null and Car-null mice but not in Pxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. Hepatic Cyp3a11 mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels of CYP3A4 and CYP2B6 (human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR- and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species.
authors.affiliation: Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Science, Tohoku University, Miyagi, Japan. masato.ohbuchi@astellas.com
authors.forename: Masato
authors.initials: M
authors.lastname: Ohbuchi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Hayato
authors.initials: H
authors.lastname: Kaneko
authors.forename: Satoru
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Inoue
authors.forename: Akio
authors.initials: A
authors.lastname: Kawamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058507:Host Specificity; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D061251:Primary Cell Culture; D011743:Pyrimidines / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics*; D011987:Receptors, Steroid / Q000172:deficiency / Q000235:genetics*; D013045:Species Specificity; D014230:Triazoles / Q000493:pharmacokinetics*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D000090702:Constitutive Androstane Receptor; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014230:Triazoles; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C496508:Cyp3a11 protein, mouse; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D065819:Voriconazole; D007654:Ketoconazole