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Negligible Effect of Ginkgo Biloba Extract on the Pharmacokinetics of Cilostazol

  • Chung, Hye-Jin (Center for Chemoinformatics Research, Korea Institute of Science and Technology) ;
  • Kim, Nam-Sun (Doping Control Center, Korea Institute of Science and Technology) ;
  • Kim, Eun-Jeong (Life Science R&D Center, SK Chemicals) ;
  • Kim, Tae-Kon (Life Science R&D Center, SK Chemicals) ;
  • Ryu, Keun-Ho (Life Science R&D Center, SK Chemicals) ;
  • Lee, Bong-Yong (Life Science R&D Center, SK Chemicals) ;
  • Kim, Dong-Hyun (Doping Control Center, Korea Institute of Science and Technology) ;
  • Jin, Chang-Bae (Doping Control Center, Korea Institute of Science and Technology) ;
  • Yoo, Hye-Hyun (Doping Control Center, Korea Institute of Science and Technology)
  • Published : 2009.07.31

Abstract

Ginkgo biloba (G. biloba) extract is a widely used phytomedicine for the oral treatment of peripheral vascular disease. Cilostazol is a synthetic antiplatelet and vasodilating agent for the treatment of intermittent claudication resulting from peripheral arterial disease. It is likely to use concomitantly G. biloba extract and cilostazol for the treatment of peripheral arterial disease, which raises a concern of increasing their adverse effects of herbal-drug interactions. To clarify any possible herbal-drug interaction between G. biloba extract and cilostazol, the effect of the G. biloba extract on the pharmacokinetics of cilostazol was investigated. As cilostazol is known to be eliminated mainly by cytochrome P450 (CYP)-mediated metabolism, we investigated the effects of G. biloba extract on the human CYP enzyme activities and the effect of G. biloba extract on the pharmacokinetics of cilostazol after co-administration of the two agents to male beagle dogs. The G. biloba extract inhibited more or less CYP2C8, CYP2C9, and CYP2C19 enzyme activities in the in vitro microsomal study with $IC_{50}$ values of 30.8, 60.5, and $25.2{\mu}g/ml$, respectively. In the pharmacokinetic study, co-administration with the G. biloba extract had no significant effect on the pharmacokinetics of cilostazol in dogs, although CYP2C has been reported to be responsible for the metabolism of cilostazol. In conclusion, these results suggest that there may not be a pharmacokinetic interaction between G. biloba extract and cilostazol.

Keywords

References

  1. Abbas, R., Chow, C. P., Browder, N. J., Thacker, D., Bramer, S. L., Fu, C. J. and Forbes, W. (2000). In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms. Hum. Exp. Toxicol. 19, 178-184 https://doi.org/10.1191/096032700678827717
  2. Akiyama, H., Kudo, S. and Shimizu, T. (1985a). The absorption, distribution and excretion of a new antithrombotic and vasodilating agent, cilostazol, in rat, rabbit, dog and man. Arzneimittelforschung 35, 1124-1132
  3. Akiyama, H., Kudo, S. and Shimizu, T. (1985b). The metabolism of a new antithrombotic and vasodilating agent, cilostazol, in rat, dog and man. Arzneimittelforschung 35, 1133-1140
  4. Aldandashi, S., Noor, R., Wang, C. X., Uddin, G. and Shuaib, A. (2007). Combination treatment with dipyridamole, aspirin, and tPA in an embolic model of stroke in rats. Exp. Neurol. 205, 563-568 https://doi.org/10.1016/j.expneurol.2007.03.018
  5. Aruna, D. and Naidu, M. U. (2007). Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects. Br. J. Clin. Pharmacol. 63, 333-338 https://doi.org/10.1111/j.1365-2125.2006.02759.x
  6. Blaisdell, J., Goldstein, J. A. and Bai, S. A. (1998). Isolation of a new canine cytochrome P450 cDNA from the cytochrome P450 2C subfamily (CYP2C41) and evidence for polymorphic differences in its expression. Drug Metab. Dispos. 26, 278-283
  7. Blumenthal, M. (2001). Herb sales down 15% in mainstream market. HerbalGram. 51, 69
  8. Blumenthal, M., Busse, W. R., Goldberg, A., Gruenwald, J., Hall, T., Riggins, C. W. and Rister, R. S. (Eds.), (1998). The complete German commission E monographs: Therapeutic guide to herbal medicines. The American Botanical Council, Austin
  9. Bramer, S. L. and Suri, A. (1999). Inhibition of CYP2D6 by quinidine and its effects on the metabolism of cilostazol. Clin. Pharmacokinet. 37(Suppl 2), 41-51
  10. Chan, P. C., Xia, Q. and Fu, P. P. (2007). Ginkgo biloba leave extract: biological, medicinal, and toxicological effects. J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev. 25, 211-244 https://doi.org/10.1080/10590500701569414
  11. Chiou, W. L. (1978). Critical evaluation of potential error in pharmacokinetic studies using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve. J. Pharmacokinet. Biopharm. 6, 539-549 https://doi.org/10.1007/BF01062108
  12. Choi, J. S., Choi, I. and Burm J. P. (2009). Effects of hydrocortisone on the pharmacokinetics of loratadine after oral and intravenous loratadine administration to rats. Biomol. Ther. 17, 205-210 https://doi.org/10.4062/biomolther.2009.17.2.205
  13. Fontana, P. and Reny, J. L. (2007). New antiplatelet strategies in atherothrombosis and their indications. Eur. J. Vasc. Endovasc. Surg. 34, 10-17 https://doi.org/10.1016/j.ejvs.2007.01.004
  14. Fugh-Berman, A. (2000). Herb-drug interactions. Lancet 355, 134-138. https://doi.org/10.1016/S0140-6736(99)06457-0
  15. Gibaldi, M. and Perrier, (1982). Pharmacokinetics. 2nd ed. Marcel-Dekker, New York
  16. Gurley, B. J., Gardner, S. F., Hubbard, M. A., Williams, D. K., Gentry, W. B., Cui, Y. and Ang, C. Y. (2005). Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging 22, 525-539 https://doi.org/10.2165/00002512-200522060-00006
  17. Hellum, B. H. and Nilsen, O. G. (2008). In vitro inhibition of CYP3A4 metabolism and p-glycoprotein-mediated transport by trade herbal products. Basic Clin. Pharmacol. Toxicol. 102, 466-475 https://doi.org/10.1111/j.1742-7843.2008.00227.x
  18. Hiratsuka, M., Hinai, Y., Sasaki, T., Konno, Y., Imagawa, K., Ishikawa, M. and Mizugaki, M. (2007). Characterization of human cytochrome P450 enzymes involved in the metabolism of cilostazol. Drug Metab. Dispos. 35, 1730-1732 https://doi.org/10.1124/dmd.107.016758
  19. Hu, Z., Yang, X., Ho, P. C., Chan, S. Y., Heng, P. W., Chan, E., Duan, W., Koh, H. L. and Zhou, S. (2005). Herb-drug interactions: a literature review. Drugs 65, 1239-1282 https://doi.org/10.2165/00003495-200565090-00005
  20. Jinno, J., Kamada, N., Miyake, M., Yamada, K., Mukai, T., Odomi, M., Toguchi, H., Liversidge, G. G., Higaki, K. and Kimura, T. (2006). Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs. J. Control. Release. 111, 56-64. https://doi.org/10.1016/j.jconrel.2005.11.013
  21. Jung, F., Mrowietz, C., Kiesewetter, H. and Wenzel, E. (1990). Effect of Ginkgo biloba on fluidity of blood and peripheral microcirculation in volunteers. Arzneimittelforschung 40, 589-593
  22. Kim, Y. S., Pyo, M. K., Park, K. M., Park, P. H., Hahn, B. S., Wu, S. J. and Yun-Choi, H. S. (1998). Antiplatelet and antithrombotic effects of combination of ticlopidine and Ginkgo biloba extract (EGb 761). Thromb. Res. 91, 33-38 https://doi.org/10.1016/S0049-3848(98)00075-9
  23. Kimura, Y., Tani, T., Kanbe, T. and Watanabe, K. (1985). Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung 35, 1144-1149
  24. Nirogi, R. V., Kandikere, V. N., Shukla, M., Mudigonda, K., Shrivasthava, W., Datla, P. V. and Yerramilli, A. (2006). Simultaneous quantification of cilostazol and its primary metabolite 3,4-dehydrocilostazol in human plasma by rapid liquid chromatography/tandem mass spectrometry. Anal. Bioanal. Chem. 384, 780-790 https://doi.org/10.1007/s00216-005-0198-z
  25. Oberpichler, H., Sauer, D., Rossberg, C., Mennel, H. D. and Krieglstein, J. (1990). PAF antagonist ginkgolide B reduces postischemic neuronal damage in rat brain hippocampus. J. Cereb. Blood Flow Metab. 10, 133-135 https://doi.org/10.1038/jcbfm.1990.17
  26. Sastre, J., Milla.n, A., Garcia de la Asuncio.n, J., Pla., R., Juan, G., Pallardo., F. V., O'Connor, E., Martin, J. A., Droy-Lefaix, M. T. and Vin.a, J. A. (1998). Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress. Free Radic. Biol. Med. 24, 298-304 https://doi.org/10.1016/S0891-5849(97)00228-1
  27. Suri, A. and Bramer, S. L. (1999). Effect of omeprazole on the metabolism of cilostazol. Clin. Pharmacokinet. 37(Suppl 2), 53-59 https://doi.org/10.2165/00003088-199937002-00006
  28. Suri, A., Forbes, W. P. and Bramer, S. L. (1999). Effects of CYP3A inhibition on the metabolism of cilostazol. Clin. Pharmacokinet. 37(Suppl 2), 61-68 https://doi.org/10.2165/00003088-199937002-00007
  29. Tucker, G. T., Houston, J. B. and Huang, S. M. (2001). Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential-towards a consensus. Br. J. Clin. Pharmacol. 52, 107-117 https://doi.org/10.1046/j.0306-5251.2001.temp.1441.x
  30. von Moltke, L. L., Weemhoff, J. L., Bedir, E., Khan, I. A., Harmatz, J. S., Goldman, P. and Greenblatt, D. J. (2004). Inhibition of human cytochromes P450 by components of Ginkgo biloba. J. Pharm. Pharmacol. 56, 1039-1044 https://doi.org/10.1211/0022357044021
  31. Zou, L., Harkey, M. R. and Henderson, G. L. (2002). Effects of herbal components on cDNA expressed cytochrome P450 enzyme catalytic activity. Life Sci. 71, 1579-1589 https://doi.org/10.1016/S0024-3205(02)01913-6

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