Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
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Effects of Kaempferol, an Antioxidant, on the Bioavailability and Pharmacokinetics of Nimodipine in Rats

  • Received : 2011.08.29
  • Accepted : 2011.10.08
  • Published : 2011.10.20
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Abstract

The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $17.1{\mu}M$. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve ($AUC_{0-\infty}$) and the peak plasma concentration ($C_{max}$) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was significantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30- to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimodipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol.

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References

  1. 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
  2. Chieli, E., Romiti, N., Cervelli, F., Tongiani, R., 1995. Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes. Life Sci. 57, 1741-1751. https://doi.org/10.1016/0024-3205(95)02152-9
  3. Choi, J.S., Burm, J.P., 2006. Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, a flavonoid, in rabbits. Arch. Pharm. Res. 29, 333-338. https://doi.org/10.1007/BF02968580
  4. 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
  5. Di Pietro, A., Conseil, G., Pérez-Victoria, J.M., Dayan, G., Baubichon- Cortay, H., Trompier, D., Steinfels, E., Jault, J.M., de Wet, H., Maitrejean, M., Comte, G., Boumendjel, A., Mariotte, A.M., Dumontet, C., McIntosh, D.B., Goffeau, A., Castanys, S., Gamarro, F., Barron, D., 2002. Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell Mol. Life Sci. 59, 307-322. https://doi.org/10.1007/s00018-002-8424-8
  6. 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
  7. Epstein, M., Loutzenhister, R.D., 1990. Effects of calcium antagonists on renal hemodynamics. Am. J. Kidney Dis. 16, 10-14.
  8. Gan, L.L., Moseley, M.A., Khosla, B., Augustijns, P.F., Bradshaw, T.P., Hendren, R.W., Thakker, D.R., 1996. 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, 344-349.
  9. Gottesman, M.M., Pastan, I., 1993. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385-427. https://doi.org/10.1146/annurev.bi.62.070193.002125
  10. Ito, K., Kusuhara, H., Sugiyama, Y., 1999. Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption theoretical approach. Pharm. Res. 16, 225-231. https://doi.org/10.1023/A:1018872207437
  11. Kazda, S., Garthoff, B., Krause, H.P., Schlossmann, K., 1982. Cerebrovascular effects of the calcium antagonistic dihydropyridine derivative nimodipine in animal experiments. Arzneimittelforschung 32, 331-338.
  12. 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
  13. Lee, H., Wang, H.W., Su, H.Y., Hao, N.J., 1994. The structureactivity relationships of flavonoids as inhibitors of cytochrome P-450 enzymes in rat liver microsomes and the mutagenicity of 2-amino-3-methyl-imidazo[4, 5-f]quinoline. Mutagenesis 9, 101-106. https://doi.org/10.1093/mutage/9.2.101
  14. Lewis, D.F.V., 1996. Cytochrome P450. Substrate specificity and metabolism. In: Cytochromes P450. Structure, Function, and Mechanism. Taylor & Francis: Bristol. 122-123.
  15. Li, C., Li, X., Choi, J.S., 2009. Enhanced bioavailability of etoposide after oral or intravenous administration with kaempferol in rats. Arch.Pharm. Res. 32, 133-138. https://doi.org/10.1007/s12272-009-1127-z
  16. Maruhn, D., Siefert, H.M., Weber, H., Ramsch, K., Suwelack, D., 1985. Pharmacokinetics of nimodipine. communication: absorption, concentration in plasma and excretion after single administration of nimodipine in rat, dog and monkey. Arzneimittelforschung 5, 1781-1786.
  17. Miean, K.H., Mohamed, S., 2001. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J. Agric. Food Chem. 49, 3106-3112. https://doi.org/10.1021/jf000892m
  18. 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.
  19. Pal, D., Mitra, A.K., 2006. MDR- and CYP3A4-mediated drugherbal interactions. Life Sci. 78, 2131-2145. https://doi.org/10.1016/j.lfs.2005.12.010
  20. Patel, J., Buddha, B., Dey, S., Pal, D., Mitra, A.K., 2004. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: changes in P-gp and CYP3A4 activity. Am. J. Ther. 11, 262-277. https://doi.org/10.1097/01.mjt.0000101827.94820.22
  21. Piao, Y., Shin, S.C., Choi, J.S., 2008. Effects of oral kaempferol on the pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, after oral administration of tamoxifen to rats. Biopharm. Drug Dispos. 29, 245-249. https://doi.org/10.1002/bdd.593
  22. Qian, M., Gallo, J.M., 1992. High-perfomance liquid chromatographic determinination of the calcium channel blocker nimodipine in monkey plasma. J. Chromatogr. 578, 316-320. https://doi.org/10.1016/0378-4347(92)80432-P
  23. Ramsch, K.D., Ahr, G., Tettenborn, D., Auer, L.M., 1985. Overview on pharmacokinetics of nimodipine in healthy volunteer and in patients with subarachnoid hemorrhage. Neurochirurgia 28, 74-78.
  24. 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
  25. Scherling, D., Buhner, K., Krause, H.P., Karl, W., Wunsche, C., 1991. Biotransformation of nimodipine in rat, dog and monkey. Arzneimittelforschung 41, 392-398.
  26. Scholz, H., 1997. Pharmacological aspects of calcium channel blockers. Cardiovasc. Drugs Ther. 10, 869-872. https://doi.org/10.1007/BF00051613
  27. Suwelack, D., Weber, H., Maruhn, D., 1985. Pharmacokinetics of nimodipine, communication: absorption, concentration in plasma and excretion after single administration of nimodipine in rat, dog and monkey. Arzneimittelforschung 35, 1787-1794.
  28. Takino, Y., Miyahara, T., Arichi, E., Arichi, S., Hayashi, T., Karikura, M., 1987. Determination of some flavonoids in Scutellariae radix by high-performance liquid chromatography. Chem. Pharm. Bull. 35, 3494-3497. https://doi.org/10.1248/cpb.35.3494
  29. Wacher, V.J., Silverman, J.A., Zhang, Y., Benet, L.Z., 1998. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci, 87, 1322-1330. https://doi.org/10.1021/js980082d
  30. Wang, Y., Cao, J., Zeng, S., 2005. Involvement of P-glycoprotein in regulating cellular levels of Ginkgo flavonols: quercetin, kaempferol, and isorhamnetin. J. Pharm. Pharmacol. 57, 751-758. https://doi.org/10.1211/0022357056299
  31. Wang, Y., Cao, J., Zeng, S., Inramonti, G., Donati, A., Chieli, E., 2004. Effects of grapefruit juice on the multidrug transporter P-glycoprotein in the human proximal tubular cell line HK-2. Life Sci. 76, 293-302. https://doi.org/10.1016/j.lfs.2004.06.015
  32. Watkins, P.B., 1996. The barrier function of CYP3A4 and P-glycoprotein in the small bowel. Adv. Pharm. Drug Deliv. Rev. 27, 161-170.