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KMID : 0941820130230030206
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Korean Journal of Clinical Pharmacy
2013 Volume.23 No. 3 p.206 ~ p.212
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Effects of Nimodipine on the Pharmacokinetics of Warfarin in Rats: A Possible Role of P-glycoprotein and CYP3A4 Inhibition by Nimodipine
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Moon Hong-Seop
Lee Chong-Ki
Burm Jin-Pil
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Abstract
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Purpose: The aim of this study was to investigate the effect of nimodipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats.
Methods: Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of nimodipine (0.5 or 2 mg/kg) in rats. The effect of nimodipine on the P-glycoprotein as well as cytochrome P450 (CYP) 3A4 activity was also evaluated.
Results: Nimodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration (IC50) of 10.2 μM. Compared to those animals in the oral control group (warfarin without nimodipine), the area under the plasma concentration?time curve (AUC) of warfarin was significantly greater (0.5 mg/kg, P<0.05; 2mg/kg, P<0.01) by 31.3-57.6%, and the peak plasma concentration (Cmax) was significantly higher (2 mg/kg, P<0.05) by 29.4% after oral administration of warfarin with nimodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.31- to 1.58-fold and the absolute bioavailability of warfarin with nimodipine was significantly greater by 64.1-76.9% compared to that in the control group (48.7%). In contrast, nimodipine had no effect on any pharmacokinetic parameters of warfarin given intravenously.
Conclusion: Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP3A4-mediated metabolism rather than P-glycoprotein-mediated efflux by nimodipine.
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KEYWORD
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nimodipine, warfarin, pharmacokinetics, P-glycoprotein, CYP3A4
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