title: Menthol reduces the anticoagulant effect of warfarin by inducing cytochrome P450 2C expression.
abstract: Recently, it was reported that the anticoagulant effect of warfarin was reduced when patients receiving warfarin also took menthol. The purpose of this study is to reveal the mechanism of this reduced anticoagulant effect of warfarin from the pharmacokinetic point of view. Warfarin was orally administered to mice 24h after the administration of menthol for 2 days, and the plasma warfarin concentration was measured. In the menthol administration group, the area under the blood concentration time curve of warfarin was decreased by approximately 25%, while total clearance was increased to 1.3-fold compared to the control group. The hepatic cytochrome P450 (CYP) 2C protein expression level in the menthol administration group was significantly increased compared to that in the control group. An increase in the nuclear translocation of constitutive androstane receptor (CAR) was also observed. The addition of menthol to human hepatic cells, HepaRG cells, caused an increase in the mRNA expression level of CYP2C9. The results of this study revealed that menthol causes an increase in CYP2C expression levels in the liver, which leads to an enhancement of warfarin metabolism, resulting in a decreased anticoagulant effect of warfarin. It was also suggested that menthol acted directly on the liver and increased the expression level of CYP2C by enhancing the nuclear translocation of CAR.
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Hoshino
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Ikarashi
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsukui
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Kurokawa
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Naito
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Yokobori
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ochiai
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kusunoki
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Risako
authors.initials: R
authors.lastname: Kon
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ochiai
authors.affiliation: Division of Applied Pharmaceutical Education and Research, Hoshi University, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Wakui
authors.affiliation: Division of Applied Pharmaceutical Education and Research, Hoshi University, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Machida
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, Japan. Electronic address: sugiyama@hoshi.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019934:International Normalized Ratio; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008610:Menthol / Q000494:pharmacology*; D008813:Mice, Inbred ICR; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D065693:Cytochrome P-450 Enzyme Inducers; C400322:cytochrome P-450 CYP2C subfamily; D008610:Menthol; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System
keywords: Constitutive androstane receptor; Cytochrome P450; Liver; Menthol; Pregnane X receptor; Warfarin