Menthol reduces the anticoagulant effect of warfarin by inducing cytochrome P450 2C expression

Hoshino, Motohiro; Ikarashi, Nobutomo; Tsukui, Makoto; Kurokawa, Asako; Naito, Rina; Suzuki, Midori; Yokobori, Kohsuke; Ochiai, Takumi; Ishii, Makoto; Kusunoki, Yoshiki; Kon, Risako; Ochiai, Wataru; Wakui, Nobuyuki; Machida, Yoshiaki; Sugiyama, Kiyoshi

doi:10.1016/j.ejps.2014.02.011

Cited by 11 publications

(11 citation statements)

References 37 publications

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“…The nuclear translocation of the nuclear receptor PXR was shown to control the expression of CYP3A2 in rats . Furthermore, a previous study reported that the translocation of PXR was enhanced after the administration of menthol to mice . In the present study, there was a disagreement in the susceptibility of CYP3A1 and CYP3A2 to menthol.…”

Section: Discussioncontrasting

confidence: 43%

Change in pharmacokinetic behavior of intravenously administered midazolam due to increased CYP3A2 expression in rats treated with menthol

Nagai

Suzuki

Yamamura

et al. 2015

Biopharm & Drug Disp

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Menthol is used widely as a constituent of functional foods and chemical drugs. The present study investigated changes in the pharmacokinetic behavior of intravenously administered midazolam (MDZ), a probe for CYP3A, when rats were treated with menthol. The study also examined which isoforms of CYP3A1 and 3A2 were menthol-inducible and contributed to the altered disposition of midazolam. Menthol was administered intraperitoneally to rats once daily for 3 days at a dose of 10 mg/kg, while the control rats received vehicle alone. The pharmacokinetic examination of i.v. administered midazolam revealed that serum midazolam concentrations at each sampling point were lower in the menthol-treated rats than in the control rats. Regarding the pharmacokinetic parameters of the menthol-treated group, the area under the curve (AUC) was decreased significantly and, correspondingly, the elimination rate constant at terminal phase (ke) was increased significantly without significant changes in the volume of distribution at steady state (Vdss). The metabolic production of the 1'-hydroxylated and 4'-hydroxylated forms of MDZ by hepatic microsomes was significantly greater in the menthol-treated rats than in the control rats. The expression levels of mRNA and protein for hepatic CYP3A2 were more than 2.5-fold higher than the control levels when the rats were treated with menthol, whereas no changes were observed in the expression levels of CYP3A1. These results indicate that menthol enhanced the elimination clearance of midazolam by inducing hepatic CYP3A2 and that careful attention should be paid when menthol is ingested in combination with drugs that act as substrates for CYP3A.

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Section: Discussioncontrasting

confidence: 43%

Change in pharmacokinetic behavior of intravenously administered midazolam due to increased CYP3A2 expression in rats treated with menthol

Nagai

Suzuki

Yamamura

et al. 2015

Biopharm & Drug Disp

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“…At this dose, the clinical reports 5,6) showing that menthol attenuated an effect of warfarin were reproducible on mice. 7) When calculated based on the amount of menthol contained in foods (cough drop, menthol content: 1-10 mg/drop) and drugs (antiperistaltic drug, menthol content: 160 mg), the dose used in this study is equivalent to 5- to 100-fold the dose for humans. It is not clear if the findings of this study can also occur in humans.…”

Section: Discussionmentioning

confidence: 99%

“…7) This study evaluated the effects of Menthol or 1% DMSO aqueous solution (control group) was orally administered to mice for 7 d. The mice were orally administered phenytoin, and the plasma concentrations of phenytoin were measured. The pharmacokinetic parameters were calculated by measuring the changes in the plasma concentrations of phenytoin after administration (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Menthol on the Pharmacokinetics of Triazolam and Phenytoin

Hoshino

Ikarashi

Hirobe

et al. 2015

Biological & Pharmaceutical Bulletin

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We have previously shown that menthol attenuates the anticoagulant effect of warfarin by increasing the expression levels of CYP3A and CYP2C in the liver. This study evaluated the effects of menthol on the pharmacokinetics of the CYP3A substrate triazolam and the CYP2C substrate phenytoin. Menthol was orally administered to mice for 7 d. Twenty-four hours after the administration of menthol, triazolam was orally administered, and the plasma concentration was measured. In addition, the CYP3A metabolic activity for triazolam and the CYP3A expression level in the liver were determined. The effects of menthol on the pharmacokinetics of phenytoin were assessed in the same manner. In the menthol-treated group, the area under the blood concentration-time curve (AUC) of triazolam was lower and its clearance was higher compared with the control group. The CYP3A metabolic activity and CYP3A expression level in the liver were significantly increased in the menthol-treated group compared with the control group. Similarly, the AUC of phenytoin was lower and the hepatic CYP2C expression level was higher in the menthol-treated group. Thus, menthol lowered the plasma concentrations of triazolam and phenytoin when concurrently administered. These effects may be attributed to an increased metabolic activity for these drugs due to the increased expression of CYP3A and CYP2C in the liver.

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“…In mice, the average daily warfarin dose for a body weight of 40 g should be 0.08 mg [6]. A Coumadin tablet contains 5 mg of warfarin.…”

Section: Methodsmentioning

confidence: 99%

Effects of propolis on warfarin efficacy

Akbay

Özenirler

Çelemli

et al. 2017

kitp

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IntroductionWarfarin is commonly used to avoid thromboembolism, predominantly for cardiovascular pathologies. However, the consumption of several herbal products is not permitted during its use due to the associated interactions. Propolis is a popular phytotherapy product made by honey bees. The use of propolis has been dramatically increasing in recent times.AimTo evaluate the possible interactions between propolis and warfarin in a mouse model with determination of the international normalized ratio (INR) values.Material and methodsCD-1 mice were employed in the experimental model. The mice were warfarinized, and propolis was administered simultaneously. The INR values were obtained. All animals were sacrificed at the end of the study.ResultsThe baseline INR value was 0.8 ±0.1. After 72 h, the INR value increased as expected. The INR value was 7.28 ±1.08 in the control group and 5.8 ±2.88 in the propolis group. At the end of the study, the INR value was 1.3 ±0.37. Propolis interacted with warfarin and caused a decrease in the INR value.ConclusionsPropolis interactions, especially with warfarin, should be kept in mind and further studied. Healthcare specialists should be aware of this possible interaction between warfarin and propolis and inform patients about it.

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Menthol reduces the anticoagulant effect of warfarin by inducing cytochrome P450 2C expression

Cited by 11 publications

References 37 publications

Change in pharmacokinetic behavior of intravenously administered midazolam due to increased CYP3A2 expression in rats treated with menthol

Change in pharmacokinetic behavior of intravenously administered midazolam due to increased CYP3A2 expression in rats treated with menthol

Effects of Menthol on the Pharmacokinetics of Triazolam and Phenytoin

Effects of propolis on warfarin efficacy

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