Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
권호 표지
DOI QR코드

DOI QR Code

Pharmacokinetic Interaction between Warfarin and Efonidipine in Rats

  • Received : 2011.07.05
  • Accepted : 2011.09.05
  • Published : 2011.10.20
Download PDF
⟨ Previous Next ⟩

Abstract

The aim of this study was to investigate the effect of efonidipine 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 efonidipine (1 or 3 mg/kg) in rats. The effect of efonidipine on the cytochrome P450 (CYP) 3A4 activity was also evaluated. Efonidipine inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of $0.08{\mu}M$. Compared to those in the oral control group (warfarin without efonidipine), the area under the plasma concentration-time curve (AUC) of warfarin was significantly greater (1 mg/kg, P<0.05; 3 mg/kg, P<0.01) by 25.9-59.0%, and the peak plasma concentration ($C_{max}$) was significantly higher (3 mg/kg, P<0.05) by 26.2% after oral administration of warfarin with efonidipine, respectively. The total body clearance of warfarin was significantly (3 mg/kg, P<0.05) decreased by efonidifine. Consequently, the relative bioavailability of warfarin was increased by 1.26- to 1.59-fold and the absolute bioavailability of warfarin with efonidipine was significantly greater by 59.7-75.4 % compared to that in the control group (47.4%). In contrast, efonidipine 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 and to reduction of total body celarance rather than renal elimination, resulting in reducing first-pass metabolism by efonidipine.

Keywords

References

  1. Abernethy, D.R., Kaminsky, L.S., 1991. Dickinson TH. Selective inhibition of warfarin metabolism by diltiazem in humans. J. Pharmacol. Exp. Ther. 257, 411-415.
  2. Benet, L.Z., Cummins, C.L., Wu, C.Y., 2003. Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr. Drug Metab. 4, 393-398. https://doi.org/10.2174/1389200033489389
  3. Bogaards, J.J., Bertrand, M., Jackson, P., Oudshoorn, M.J., Weaver, R.J., van Bladeren, P.J., Walther, B., 2000. Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica 30, 1131-1152. https://doi.org/10.1080/00498250010021684
  4. Cao, X., Gibbs, S.T., Fang, L., Miller, H.A., Landowski, C.P., Shin, H.C., Lennernas, H., Zhong, Y., Amidon, G.L., Yu, L.X., Sun, D., 2006. Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm. Res. 23, 1675-1686. https://doi.org/10.1007/s11095-006-9041-2
  5. Choi, D.H., Chang, K.S., Hong, S.P., Choi, J.S., 2008. Effect of atrovastatin on intravenous and oral pharmacokinetics of verapamil in rats. Biopharm. Drug Dispos. 29, 45-50. https://doi.org/10.1002/bdd.582
  6. Choi, J.S., Piao, Y.J., Han, H.K., 2006. Phatmacokinetics interaction between fluvastatin and diltiazem in rats. Biopharm. Drug Dispos. 27, 437-441. https://doi.org/10.1002/bdd.521
  7. Cummins, C.L., Jacobsen, W., Benet, L.Z., 2002. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther. 300, 1036-1045. https://doi.org/10.1124/jpet.300.3.1036
  8. Darvari, R., Boroujerdi, M., 2004. Concentration dependency of modulatory effect of amlodipine on P-glycoprotein efflux activity of doxorubicin - a comparison with tamoxifen. J. Pharm. Pharmacol. 56, 985-991. https://doi.org/10.1211/0022357043941
  9. Guengerich, F.P., Martin, M.V., Beaune, P.H., Kremers, P., Wolff, T., Waxman, D.J., 1986. Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J. Biol. Chem. 261, 5051-5060.
  10. Harmsze, A.M., Robijns, K., van Werkum, J.W., Breet, N.J., Hackeng, C.M., Ten Berg, J.M., Ruven, H.J., Klungel, O.H., de Boer, A., Deneer, V.H., 2010. The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response. Thromb Haemost. 103, 920-925. https://doi.org/10.1160/TH09-08-0516
  11. Hirsh, J., Dalen, J.E., Anderson, D.R., Poller, L., Bussey, H., Ansell, J., Deykin, D., Brandt, J.T., 1998. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 114, 445-469. https://doi.org/10.1378/chest.114.5_Supplement.445S
  12. Holford, N.H.G., 1986. Clinical pharmacokinetics and pharmacodynamics of warfarin: understanding the dose-effect relationship. Clin. Pharmacokinet. 11, 483-504. https://doi.org/10.2165/00003088-198611060-00005
  13. Kaminsky, L.S., Zhang, Z.Y., 1997. Human P450 metabolism of warfarin. Pharmacol. Ther. 73, 67-74. https://doi.org/10.1016/S0163-7258(96)00140-4
  14. Kelly, P.A., Wang, H., Napoli, K.L., Kahan, B.D., Strobel, H.W., 1999. Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur. J. Drug. Metab. Pharmacokinet. 24, 321-328. https://doi.org/10.1007/BF03190040
  15. Kim, M.J., Nafziger, A.N., Kashuba, A.D., Kirchheiner, J., Bauer, S., Gaedigk, A., Bertino, J.S. Jr., 2006. Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin. Eur. J. Clin. Pharmacol. 62, 431-436. https://doi.org/10.1007/s00228-006-0124-0
  16. Lewis, D.F.V., 1996. Cytochrome P450. Substrate specificity and metabolism. In: Cytochromes P450. Structure, Function, and Mechanism. Taylor & Francis: Bristol: 122-123.
  17. Lilja, J.J., Backman, J.T., Neuvonen, P.J., 2005. Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects. Br. J. Clin. Pharmacol. 59, 433-439. https://doi.org/10.1111/j.1365-2125.2004.02323.x
  18. Masuda, Y., Takeguchi, M., Arakawa, C., Sakai, T., Hibi M., Tanaka, S., Shigenobu, K., Kasuya, Y., 1990. Antihypertensive and diuretic effects of NZ-105, a novel dihydropyridine derivative. Arch. Int. Pharmacodyn. Ther. 304, 247-264.
  19. Mungall, D.R., 1985. Population pharmacokinetics of racemic warfarin in adult patients. J. Pharmacokinet. Biopharm. 13, 213-227. https://doi.org/10.1007/BF01065653
  20. Nakabeppu, H., Asada, M., Oda, T., Shinozaki, Y., Yajima, T., 1996. Plasma and urinary metabolites of efonidipine hydrochloride in man. Xenobiotica 26, 229-239. https://doi.org/10.3109/00498259609046703
  21. Nishio, S., Watanabe, H., Kosuge, K., Uchida, S., Hayashi, H., Ohashi, K., 2005. Interaction between amlodipine and simvastatin in patients with hypercholesterolemia and hypertension. Hypertens. Res. 28, 223-227. https://doi.org/10.1291/hypres.28.223
  22. Saeki, T., Ueda, K., Tanigawara, Y., Hori, R., Komano, T., 1993. Pglycoprotein- mediated transcellular transport of MDR-reversing agents. FEBS Lett. 324, 99-102. https://doi.org/10.1016/0014-5793(93)81540-G
  23. Scordo, M.G., Pengo, V., Spina, E., Dahl, M.L., Gusella, M., Padrini, R., 2002. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin. Pharmacol. Ther. 72, 702-710. https://doi.org/10.1067/mcp.2002.129321
  24. Shimizu, M., Ogawa, K., Sasaki, H., Uehara, Y., Otsuka, Y., Okumura, H., Kusaka, M., Hasuda, T., Yamada, T., Mochizuki, S., 2003. Effects of efonidipine, an L- and T-Type dual calcium channel blocker, on heart rate and blood pressure in patients with mild to severe hypertension: an uncontrolled, open-label pilot study. Current Ther. Res. 64, 707-714. https://doi.org/10.1016/j.curtheres.2003.11.004
  25. Stoysich, A.M., Lucas, B.D., Mohiuddin, S.M., Hilleman, D.E., 1996. Further elucidation of pharmacokinetic interaction between diltiazem and warfarin. Int. J. Clin. Pharmacol. Ther. 34, 56-60.
  26. Tamura, T., Saigusa, A., Kokubun, S., 1991. Mechanisms underlying the slow onset of action of a new dihydropyridine, NZ-105, on a cultured smooth muscle cell line. Naunyn. Schmiedebergs. Arch. Pharmacol. 343, 405-410.
  27. Tanaka, T., Tsutamoto, T., Sakai, H., Fujii, M., Yamamoto, T., Horie, M., 2007. Comparison of the effects of efonidipine and amlodipine on aldosterone in patients with hypertension. Hypertens. Res. 30, 691-697. https://doi.org/10.1291/hypres.30.691
  28. Wacher, V.J., Salphati, L., Benet, L.Z., 2001. Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Deliv. Rev. 46, 89-102. https://doi.org/10.1016/S0169-409X(00)00126-5
  29. Wallin, R., Sane, D.C., Hutson, S.M., 2002. Vitamin K 2,3-epoxide reductase and the vitamin K-dependent gamma-carboxylation system. Thromb Res. 108, 221-226. https://doi.org/10.1016/S0049-3848(03)00060-4
  30. Yusa, K., Tsuruo, T., 1989. Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells. Cancer Res. 49, 5002-5006.
  31. Zhu, M., Chan, K.W., Ng, L.S., Chang, Q., Chang, S., Li, R.C., 1999. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J. Pharm. Pharmacol. 51, 175-180. https://doi.org/10.1211/0022357991772105