와파린의 약물동태학에 니모디핀의 영향
Effects of Nimodipine on the Pharmacokinetics of Warfarin in Rats: A Possible Role of P-glycoprotein and CYP3A4 Inhibition by Nimodipine
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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; 2 mg/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 CYP 3A4-mediated metabolism rather than P-glycoprotein-mediated efflux by nimodipine.
Abstract
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; 2 mg/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 CYP 3A4-mediated metabolism rather than P-glycoprotein-mediated efflux by nimodipine.
참고문헌 (31)
- Kazda S, "Cerebrovascular effects of the calcium antagonistic dihydropyridine derivative nimodipine in animal experiments", Arzneimittelforschung, 32, pp.331~338 (1982)
- Epstein, M, "Effects of calcium antagonists on renal hemodynamics", Am J Kidney Dis, 16, pp.10~14 (1990)
- 김양우, "티크로피딘과 니모디핀과의 약동학적 상호작용", 한국임상약학회지, 20(3), pp.200~204 (2010), 한국임상약학회
- Maruhn D, "Pharmacokinetics of nimodipine. communication: absorption, concentration in plasma and excretion after single administration of nimodipine in rat, dog and monkey", Arzneimittelforschung, 5, pp.1781~1786 (1985)
- Suwelack D, "Pharmacokinetics of nimodipine, communication: absorption, concentration in plasma and excretion after single administration of nimodipine in rat, dog and monkey", Arzneimittelforschung, 35, pp.1787~1794 (1985)
- Saeki T, "P-glycoproteinmediated transcellular transport of MDR-reversing agents", FEBS Lett, 324, pp.99~102 (1993)
- Wacher VH, "Role of Pglycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics", J Pharm Sci, 87, pp.1322~1330 (1998)
- Gottesman MM, "Biochemistry of multidrug resistance mediated by the multidrug transporter", Annu Rev Biochem, 62, pp.385~427 (1993)
- Gan LL, "CYP3A-Like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells: interaction between the two biochemical barriers to intestinal transport", Drug Metab Dispos, 24, pp.344~349 (1996)
- Ito K, "Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption theoretical approach", Pharm Res, 16, pp.225~231 (1999)
- Watkins PB, "The barrier function of CYP3A4 and Pglycoprotein in the small bowel", Adv. Pharm. Drug Deliv Rev, 27, pp.161~170 (1996)
- Hirsh J, "Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range", Chest, 114, pp.445~469 (1998)
- Wallin R, "Vitamin K 2,3-epoxide reductase and the vitamin K-dependent gamma-carboxylation system", Thromb Res, 108, pp.221~226 (2002)
- Mungall DR, "Population pharmacokinetics of racemic warfarin in adult patients", J Pharmacokinet Biopharm, 13, pp.213~227 (1985)
- Holford NHG, "Clinical pharmacokinetics and pharmacodynamics of warfarin : understanding the dose-effect relationship", Clin Pharmacokinet, 11, pp.483~504 (1986)
- Scordo MG, "Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance", Clin Pharmacol Ther, 72, pp.702~710 (2002)
- Kaminsky LS, "Human P450 metabolism of warfarin", Pharmacol Ther, 73, pp.67~74 (1997)
- Zhu M, "Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats", J Pharm Pharmacol, 51, pp.175~180 (1999)
- Crespi CL, "Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450", Ana Biochem, 248, pp.188~190 (1997)
- Han CY, "Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells", Carcinogenesis, 29, pp.1837~1844 (2008)
- Cummins CL, "Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4", J Pharmacol Exp Ther, 300, pp.1036~1045 (2002)
- Benet LZ, "Transporter-enzyme interactions : implications for predicting drug–drug interactions from in vitro data", Curr Drug Metab, 4, pp.393~398 (2003)
- Darvari R, "Concentration dependency of modulatory effect of amlodipine on P-glycoprotein efflux activity of doxorubicin-a comparison with tamoxifen", J Pharm Pharmacol, 56, pp.985~991 (2004)
- Wacher VJ, "Active secretion and enterocytic drug metabolism barriers to drug absorption", Adv Drug Deliv Rev, 46, pp.89~102 (2001)
- 이준한, "토끼에서 나린진이 니모디핀의 생체이용률에 미치는 영향", 한국임상약학회지, 18(2), pp.120~123 (2008), 한국임상약학회
- Dong-Hyun Choi, "Effects of Amlodipine on the Pharmacokinetics of Warfarin after Oral and Intravenous Administration of Warfarin in Rats", 응용약물학회지, 19(4), pp.493~497 (2011), 한국응용약물학회
- Choi JS, "Phatmacokinetics interaction between fluvastatin and diltiazem in rats", Biopharm Drug Dispos, 27, pp.437~441 (2006)
- Yusa K, "Reversal mechanism of multidrug resistance by verapamil : direct binding of verapamil to Pglycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562", ADM cells, 1989, pp.49, 5002~5006
- Harmsze AM, "The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response", Thromb Haemos, 103, pp.920~925 (2010)
- Abernethy DR, "Selective inhibition of warfarin metabolism by diltiazem in humans", J Pharmacol Exp Ther, 257, pp.411~415 (1991)
- Stoysich AM, "Further elucidation of pharmacokinetic interaction between diltiazem and warfarin", Int J Clin Pharmacol Ther, 34, pp.56~60 (1996)