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KMID : 0606920110190040493
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Biomolecules & Therapeutics
2011 Volume.19 No. 4 p.493 ~ p.497
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Effects of Amlodipine on the Pharmacokinetics of Warfarinafter Oral and Intravenous Administration of Warfarin in Rats
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Choi Dong-Hyun
Piao Yong Ji
Choi Eun-Joo
Choi Jun-Shik
Burm Jin-Pil
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Abstract
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The aim of this study was to investigate the effect of amlodipine on the pharmacokinetics of warfarin after oral and intravenous administration of warfarin in rats. Warfarin was administered orally (0.2 mg/kg) or intravenously (0.05 mg/kg) without or with oral administration of amlodipine (0.1 or 0.4 mg/kg) in rats. The effect of amlodipine on the P-glycoprotein (P-gp) as well as cytochrome P450 (CYP) 3A4 activity was also evaluated. Amlodipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration (IC50) of 9.1 μM. Compared to those animals in the oral control group (warfarin without amlodipine), the area under the plasma concentration-time curve (AUC) of warfarin was signifi cantly greater (0.1 mg/kg, p<0.05; 0.4 mg/kg, p<0.01) by 26.5-53.5%, and the peak plasma concentration (Cmax) was signifi cantly higher (0.4 mg/kg, p<0.05) by 26.2% after oral administration of warfarin with amlodipine, respectively. Consequently, the relative bioavailability of warfarin increased by 1.26- to 1.53-fold and the absolute bioavailability of warfarin with amlodipine was signifi cantly greater by 61.7-72.5% compared to that in the control group (47.4%). In contrast, amlodipine had no effect on any pharmacokinetic parameters of warfarin given intravenously. Therefore, the enhanced oral bioavailability of warfarin may be due to inhibition of CYP 3A4-mediated metabolism in the intestine and/or liver rather than renal elimination and P-gp by amlodipine.
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KEYWORD
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Amlodipine, Warfarin, Pharmacokinetics, P-glycoprotein, CYP3A4, Rats
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