Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
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Effects of Silibinin on the Pharmacokinetics of Carvedilol after Oral Administration in Rats

  • Received : 2011.04.08
  • Accepted : 2011.05.23
  • Published : 2011.06.20
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Abstract

This study was designed to investigate the effects of silibinin on the pharmacokinetics of carvedilol after oral administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) with oral silibinin (0.3, 1.5 or 6 mg/kg) and intravenously (1 mg/kg) to rats. The effects of silibinin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 and CYP2D6 activity were also evaluated. Silibinin inhibited CYP2C9 and CYP2D6 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 5.2 ${\mu}M$ and 85.4 ${\mu}M$, respectively. In addition, silibinin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the area under the plasma concentration-time curve was significantly increased by 36.3-57.1%, and the peak concentration was significantly increased by 51.1-88.5% in the presence of silibinin after oral administration of carvedilol. Consequently, the relative bio-availability of carvedilol was increased by 1.13- to 1.57-fold and the absolute bioavailability was significantly increased by 38.6-59.7%. The time to reach peak concentration and the terminal half-life were not significant. The enhanced oral bio-availability of carvedilol may result from inhibition of CYP2C9-mediated metabolism and P-gp-mediated efflux of carvedilol rather than inhibition of CYP2D6-mediated metabolism in the intestine and/or in the liver by silibinin.

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References

  1. Abshagen, U., 1987. A new molecule with vasodilating and ${\beta}$-adrenoceptor blocking properties. J. Cardiovasc. Pharmacol. 10, 23-32.
  2. Alarcon de la Lastra, C., Martin, M.J., Motilva, V., 1994. Antiulcer and gastroprotective effects of quercetin: a gross and histologic study. Pharmacology 48, 5662.
  3. 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., Hendrikse, N.H., 2005. New positron emission tomography tracer [(11)C]carvedilol reveals P-glycoprotein modulation kinetics. Br. J. Pharmacol. 145, 1045-51. https://doi.org/10.1038/sj.bjp.0706283
  4. 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
  5. 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., 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
  6. Bristow, M.R., Larrabee, P., Minobe, W., Roden, R., Skerl, L., Klein, J., Handwerger, D., Port, J.D., Müller-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
  7. 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
  8. Cleland, J.G., Bristow, M.R., Erdmann, E., Remme, W.J., Swedberg, K., 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
  9. Cournot, A., Lim, C., Duchier, J., Safar, M., 1992. Hemodynamic effects of carvedilol after acute oral administration in hypertensive and normal subjects. J. Cardiovasc. Pharmacol. 19, S35-39.
  10. 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
  11. 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
  12. DasGupta, P., Broadhurst, P., Lahiri, A., 1991. The effects of intravenous carvedilol, a new multiple action vasodilatory betablocker, in congestive heart failure. J. Cardiovasc. Pharmacol. 18, S12-16.
  13. Dixon, R.A., Steel, C.L., 1999. Flavonoids and isoflavonoids - a gold mine for metabolic engineering. Trend Plant. Sci. 4, 394-400. https://doi.org/10.1016/S1360-1385(99)01471-5
  14. Dzubak, P., Hajduch, M., Gazak, R., Svobodova, A., Psotova, J., Walterova, D., Sedmera, P., Kren, V., 2006. New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity. Bioorg. Med. Chem. 14, 3793-3810. https://doi.org/10.1016/j.bmc.2006.01.035
  15. Feuerstein, G.Z., Bril, A., 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
  16. Frishman, W.H., 1998. Carvedilol. N. Engl. J. Med. 339, 1759-1765. https://doi.org/10.1056/NEJM199812103392407
  17. 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
  18. Kaminsky, L.S., Fasco, M.J., 1991. Small intestinal cytochromes P450. Crit. Rev. Toxicol. 21, 407-422.
  19. Katiyar, S.K., Korman, N.J., Mukhtar, H., Agarwal, R., 1997. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J. Natl. Cancer Inst. 89, 556-566. https://doi.org/10.1093/jnci/89.8.556
  20. Kolars, J.C., Schmiedlin-Ren, P., Schuetz, J.D., Fang, C., 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. Kosina, P., Maurel, P., Ulrichova, J., Dvorak, Z., 2005. Effect of silybinin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytes. J. Biochem. Mol. Toxicol. 19, 149-153. https://doi.org/10.1002/jbt.20066
  22. Lewis, D.F.V., 1996. Cytochrome P450. Substrate specificity and metabolism. In: Cytochromes P450. Structure, Function, and Mechanism. Taylor & Francis: Bristol. 122-123.
  23. Lund-Johansen, P., Omvik, P., Nordrehaug, J.E., 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
  24. McTavish, D., Campoli-Richards, D., Sorkin, E.M., 1993. Carvedilol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 45, 232-58.
  25. Morazzoni, P., Bombardelli, E., 1995. Silybum marianum (fitoterapia). Fitoterapia 66, 3-42.
  26. Morgan, T., 1994. Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin. Pharmacokinet. 26, 335-346. https://doi.org/10.2165/00003088-199426050-00002
  27. Neugebauer, G., Akpan, W., von Mollendorff, E., Neubert, P., Reiff, K., 1987. Pharmacokinetics and disposition of carvedilol in humans. J. Cardiovasc. Pharmacol. 11, S85-88.
  28. Neugebauer, G., Neubert, P., 1991. Metabolism of carvedilol in man. Eur. J. Drug Metab. Pharmacokinet. 16, 257-260. https://doi.org/10.1007/BF03189969
  29. Nijveldt, R.J., van Nood, E., van, Hoorn, D.E., Boelens, P.G., van Norren, K., van Leeuwen, P.A., 2001. Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr. 74, 418-425.
  30. Ohnishi, E., Bannai, H., 1993. Quercetin potentiates TNF-induced antiviral activity. Antiviral Res. 22, 327-331. https://doi.org/10.1016/0166-3542(93)90041-G
  31. Oldham, H.G., Clarke, S.E., 1997. In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol. Drug Metab. Dispos. 25, 970-977.
  32. 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
  33. Takahama, U., 1985. Inhibition of lipoxygenase-dependent lipid peroxidation by quercetin: mechanism of antioxidative function. Phytochemistry 24, 1443-1446. https://doi.org/10.1016/S0031-9422(00)81040-7
  34. von Mollendorff, E., Abshagen, U., Akpan, W., Neugebauer, G., Schroter, E., 1986. Clinical pharmacologic investigations with carvedilol, a new beta-blocker with direct vasodilator activity. Clin. Pharmacol. Ther. 39, 677-682. https://doi.org/10.1038/clpt.1986.118
  35. Zhao, J., Lahiri-Chatterjee, M., Sharma, Y., Agarwal, R., 2000. Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis 21, 811-816. https://doi.org/10.1093/carcin/21.4.811
  36. Zharghi, A., Foroutan, S.M., Shafaati, A., 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
  37. Zuber, R., Modriansky, M., Dvorak, Z., Rohovsky, P., Ulrichova, J., Simanek, V., Anzenbacher, P., 2002. Effect of silybinin and its congeners on human liver microsomal cytochrome P450 activities. Phytother. Res. 16, 632-638. https://doi.org/10.1002/ptr.1000