DOI QR코드

DOI QR Code

Pharmacokinetic Drug Interaction between Carvedilol and Ticlopidine in Rats

  • Received : 2010.03.31
  • Accepted : 2010.07.07
  • Published : 2010.07.31

Abstract

This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $25.2\;{\mu}M$. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p<0.05) increased by 14-41%, and the peak concentration ($C_{max}$) was significantly (12 mg/kg, p<0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14- to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

Keywords

References

  1. Bart, J., Dijkers, E. C., Wegman, T. D., de Vries, E. G., van der Graaf, W. T., Groen, H. J., Vaalburg, W., Willemsen, A. T. and Hendrikse, N. H. (2005). New positron emission tomography tracer [(11)C]carvedilol reveals P-glycoprotein modulation kinetics. Br. J. Pharmacol. 145, 1045-1051. https://doi.org/10.1038/sj.bjp.0706283
  2. Bristow, M. R., Gilbert, E. M., Abraham, W. T., Adams, K. F., Fowler, M. B., Hershberger, R. E., Kubo, S. H., Narahara, K. A., Ingersoll, H., Krueger, S., Young, S. and Shusterman, N. (1996). Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 94, 2807-2816. https://doi.org/10.1161/01.CIR.94.11.2807
  3. Bristow, M. R., Larrabee, P., Minobe, W., Roden, R., Skerl, L., Klein, J., Handwerger, D. and Port, J. D., Muller-Beckmann B. (1992). Receptor pharmacology of carvedilol in the human heart. J. Cardiovasc. Pharmacol. 19, S68-80. https://doi.org/10.1097/00005344-199219001-00014
  4. Buur, T., Larsson, R., Berglund, U., Donat, F. D. V. M. and Tronquet, C. (1997). Pharmocokinetics and effect of ticlopidine on platelet aggregation in subjects with normal and impaired renal function. J. Clin. Pharmacol. 37, 108-115. https://doi.org/10.1002/j.1552-4604.1997.tb04768.x
  5. 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. and 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
  6. Cleland, J. G., Bristow, M. R., Erdmann, E., Remme, W. J., Swedberg, K. and Waagstein, F. (1996). Beta-blocking agents in heart failure. Should they be used and how? Eur. Heart J. 17, 1629-1639. https://doi.org/10.1093/oxfordjournals.eurheartj.a014745
  7. Cournot, A., Lim, C., Duchier, J. and Safar, M. (1992). Hemodynamic effects of carvedilol after acute oral administration in hypertensive and normal subjects. J. Cardiovasc. Pharmacol. 19, S35-39.
  8. Crespi, C. L., Miller, V. P., Penman, B. W. (1997). Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem. 248, 188-190. https://doi.org/10.1006/abio.1997.2145
  9. DasGupta, P., Broadhurst, P. and Lahiri, A. (1991). The effects of intravenous carvedilol, a new multiple action vasodilatory beta-blocker, in congestive heart failure. J. Cardiovasc. Pharmacol. 18, S12-16. https://doi.org/10.1097/00005344-199106183-00007
  10. Feuerstein, G. Z., Bril, A. and Ruffolo, R. R. Jr. (1997). Protective effects of carvedilol in the myocardium. Am. J. Cardiol. 80, 41L-45L. https://doi.org/10.1016/S0002-9149(97)00847-3
  11. Gent, M., Blakely, J. A., Easton, J. D., Ellis, D. J., Hachinski, V. C., Harbison, J. W., Panak, E., Roberts, R. S., Sicurella, J. and Turpie, A. G. (1989). The Canadian American ticlopidine study (CATS) in thromboembolic stroke. Lancet. 1, 1215-1220.
  12. Gidal, B. E., Sorkness, C. A., McGill, K. A., Larson, R. and Levine, R. R. (1995). Evaluation of a potential enantioselective interaction between ticlopidine and warfarin in chronically anticoagulated patients. Ther. Drug Monit. 17, 33-38. https://doi.org/10.1097/00007691-199502000-00006
  13. Hampton, J. R. (1996). Beta-blockers in heart failure--the evidence from clinical trials. Eur. Heart J. 17, 17-20. https://doi.org/10.1093/eurheartj/17.suppl_B.17
  14. Hass, W. K., Easton, J. D., Adams, H. P. Jr., Pryse-Phillips, W., Molony, B. A., Anderson, S. and Kamm, B. (1989). A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N. Engl. J. Med. 321, 501-507. https://doi.org/10.1056/NEJM198908243210804
  15. Haynes, R. B., Sandler, R. S., Larson, E. B., Pater, J. L. and Yatsu, F. M. (1998). A critical appraisal of ticlopidine, a new antiplatelet agent. Effectiveness and clinical indications for prophylaxis of atherosclerotic events. Arch. Intern. Med. 152, 1376-1380.
  16. Ito, M. K., Smith, A. R. and Lee, M. L. (1992). Ticlopidine: a new platelet aggregation inhibitors. Clin. Pharm. 11, 603-617.
  17. Janzon, L., Bergqvist, D., Boberg, J., Boberg, M., Eriksson, I., Lindgarde, F., Persson, G., Almgren, B., Fagher, B. and Kjellstrom, T., et al. (1990). Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J. Intern. Med. 227, 301-308. https://doi.org/10.1111/j.1365-2796.1990.tb00164.x
  18. Kaminsky, L. S. and Fasco M. J. (1991). Small intestinal cytochromes P450. Crit. Rev. Toxicol. 21, 407-422.
  19. Ko, J. W., Desta, Z., Soukhova, N. V., Tracy, T. and Flockhart, D. A. (2000). In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C9 and CYP2D6. Br. J. Clin. Pharmacol. 49, 343-351.
  20. Kolars, J. C., Schmiedlin-Ren, P., Schuetz, J. D., Fang, C. and Watkins, P. B. (1992). Identification of rifampin-inducible P450IIIA4 (CYP2C9) in human small bowel enterocytes. J. Clin. Invest. 90, 1871-1878. https://doi.org/10.1172/JCI116064
  21. Lewis, D. F. V. (1996). Cytochrome P450. Substrate specificity and metabolism. In Cytochromes P450. Structure, Function, and Mechanism, pp. 122-123. Taylor & Francis, Bristol.
  22. Lund-Johansen, P., Omvik, P., Nordrehaug, J. E. and White, W. (1992). Carvedilol in hypertension: effects on hemodynamics and 24-hour blood pressure. J. Cardiovasc. Pharmacol. 19, S27-34. https://doi.org/10.1097/00005344-199219001-00007
  23. McGinnity, D., Tucker, J., Trigg, S. and Riley, R. (2005). Prediction of CYP2C9-mediated drug-drug interactions: a comparison using data from recombinant enzymes and human hepatocytes. Drug Metab. Dispos. 33, 1700-1707. https://doi.org/10.1124/dmd.105.005884
  24. McTavish, D., Campoli-Richards, D. and Sorkin, E. M. (1993). Carvedilol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 45, 232-258.
  25. Morgan, T. (1994). Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin. Pharmacokinet. 26, 335-346. https://doi.org/10.2165/00003088-199426050-00002
  26. Neugebauer, G., Akpan, W., von Mollendorff, E., Neubert, P. and Reiff, K. (1987). Pharmacokinetics and disposition of carvedilol in humans. J. Cardiovasc. Pharmacol. 11, S85-88.
  27. Neugebauer, G. and Neubert, P. (1991). Metabolism of carvedilol in man. Eur. J. Drug Metab. Pharmacokinet. 16, 257-260. https://doi.org/10.1007/BF03189969
  28. Oldham, H. G. and Clarke, S. E. (1997). In vitro identification of the human cytochrome P450 enzymes involved in the meta-bolism of R(+)- and S(-)-carvedilol. Drug Metab. Dispos. 25, 970-977.
  29. Saeki, T., Ueda, K., Tanigawara, Y., Hori, R. and Komano, T. (1993). P-glycoprotein-mediated transcellular transport of MDR-reversing agents. FEBS. Lett. 324, 99-102. https://doi.org/10.1016/0014-5793(93)81540-G
  30. Saltiel, E. and Ward, A. (1987). Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutics efficacy in platelet-dependent disease states. Drugs 34, 222-262. https://doi.org/10.2165/00003495-198734020-00003
  31. Shah, J., Fratis, A., Ellis, D., Murakami, S. and Teitelbaum, P. (1990). Effect of food and antacid on absorption of orally administered ticlopidine hydrochloride. J. Clin. Pharmacol. 30, 733-736. https://doi.org/10.1002/j.1552-4604.1990.tb03635.x
  32. Solomon, D. H. and Hart, R. G. (1994). Antithrombotic therapies for stroke prevention. Curr. Opin. Neurol. 7, 48-53. https://doi.org/10.1097/00019052-199402000-00009
  33. Verhaeghe, R. (1991). Prophylactic antiplatelet therapy in peripheral arterial disease. Drugs 42, 51-57.
  34. Zarghi, A., Foroutan, S. M., Shafaati, A. and Khoddam, A. (2007). Quantification of carvedilol in human plasma by liquid chromatography using fluorescence detection: application in pharmacokinetic studies. J. Pharm. Biomed. Anal. 44, 250-253. https://doi.org/10.1016/j.jpba.2007.01.026

Cited by

  1. Effects of Glipizide on the Pharmacokinetics of Carvedilol after Oral and Intravenous Administration in Rats vol.19, pp.2, 2011, https://doi.org/10.4062/biomolther.2011.19.2.237
  2. P-Glycoprotein vol.21, pp.1, 2014, https://doi.org/10.1097/MJT.0000000000000014
  3. The P-Glycoprotein Transport System and Cardiovascular Drugs vol.61, pp.25, 2013, https://doi.org/10.1016/j.jacc.2013.02.058