Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, a flavonoid, in rabbits

  • Jun Shik Choi
  • Jin Pil Burm
Articles Drug Development


The aim of this study was to investigate the effect of morin on the bioavailability of nimodipine after administering nimodipine (15 mg/kg) orally to rabbits either co-administered or pretreated with morin (2, 10 and 20 mg/kg). The plasma concentrations of nimodipine in the rabbits pretreated with morin were increased significantly (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg) compared with the control, but the plasma concentrations of nimodipine co-administered with morin were not significant. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (Cmax) of the nimodipine in the rabbits pretreated with morin were significantly higher (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg), but only the Cmax of nimodipine co-administered with morin 10 mg/kg was increased significantly (p<0.05). The absolute bioavailability (A.B%) of nimodipine in the rabbits pretreated with morin was significantly (p<0.05 at 10 mg/kg, p<0.01 at 20 mg/kg) higher (54.1–65.0%) than the control (36.7%). The increased bio-availability of nimodipine in the rabbits pretreated with morin might have been resulted from the morin, which inhibits the efflux pump P-glycoprotein and the first-pass metabolizing enzyme by cytochrome P-450 3A4 (CYP 3A4).

Key words

Nimodipine Morin Bioavailability P-Glycoprotein Cytochrome P-450 3A4 


  1. Choi, H. J. and Choi, J. S., Effects of morin pretreatment on the pharmacokinetics of diltiazem and its major metabolite, desacetyldiltiazem in rats.Arch. Pharm. Res., 28, 970–976 (2005a).PubMedCrossRefGoogle Scholar
  2. Choi, J. S. and Han, H. K., Pharmacokinetic interaction between diltiazem and morin, a flavonoid, in rats.Pharmacol. Res., 52, 386–391 (2005b).PubMedCrossRefGoogle Scholar
  3. Dixon, R. A., and Steele, C. L., Flavonoids and isoflavonoids—a gold mine for metabolic engineering.Trends Plant Sci., 4, 394–400 (1999).PubMedCrossRefGoogle Scholar
  4. Epstein, M. and Loutzenhister, R. D., Effects of calcium antagonists on renal hemodynamics,Am. J. Kidney Dis., 16, 10–14 (1990).PubMedGoogle Scholar
  5. Fang, S. H., Hou, Y. C., Chang, W. C., Hsiu, S. L., Chao, P. D. L., and Chiang, B. L., Morin sulfates glucuronides exert anti-inflammatory activity on activated macrophages and decreased the incidence of septic shock.Life Sci. 74, 743–756 (2003).PubMedCrossRefGoogle Scholar
  6. Francis, A. R., Shetty, T. K., and Bhattacharya, R. K., Modulating effect of plant flavonoids on the mutagenicity of N-methyl-N-nitro-N-nitrosoguanidine.Carcinogenesis, 10, 1953–1955 (1989).PubMedCrossRefGoogle Scholar
  7. Gan, L. L., Moseley, M. A., Khosla, B., Augustijns, P. F., Bradshaw, T. P., Hendren, R. W., and Thakker, D. R., 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 (1996).PubMedGoogle Scholar
  8. Gottesman, M. M. and Pastan, I., Biochemistry of multidrug resistance mediated by the multidrug transporter.Annu. Rev. Biochem., 62, 385–427 (1993).PubMedCrossRefGoogle Scholar
  9. Guengerich, F. P., Brian, W. R., Iwasaki, M., Sari, M. A., Baarnhielm, C., and Berntssom, P., Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrom P-450 3A4,J. Med. Chem., 34, 1834–1844 (1991).CrossRefGoogle Scholar
  10. Hanasaki, Y., Ogawa, S., and Fukui, S., The correlation between active oxygens scavenging and antioxidative effects of flavonoids.Free Radic. Biol. Med. 16, 845–850 (1994).PubMedCrossRefGoogle Scholar
  11. Hodek, P., Trefil, P., and Stiborova, M., Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450.Chem. Biol. Interact., 139, 1–21 (2002).PubMedCrossRefGoogle Scholar
  12. Hsiu, S. L., Hou, Y. C., Wang, Y. H., Tsao, C. W., Su, S. F., and Chao, P. D., Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats.Life Sci., 72, 227–235 (2002).PubMedCrossRefGoogle Scholar
  13. Ito, K., Kusuhara, H., and Sugiyama, Y., Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption theoretical approach.Pharm. Res., 16, 225–231 (1999).PubMedCrossRefGoogle Scholar
  14. Kazda, S., Garthoff, B., Krause, H. P., and Schlossmann, K., Cerebrovascular effects of the calcium antagonistic dihydropyridine derivative nimodipine in animal experiments,Arzneimittelforschung., 32, 331–338 (1982).PubMedGoogle Scholar
  15. Maruhn, D., Siefert, H. M., Weber, H., Ramsch, K., and Suwelack, D., Pharmacokinetics of nimodipine. communication: absorption, concentration in plasma and excretion after single administration of nimodipine in rat, dog and monkey,Arzneimittelforschung., 35, 1781–1786 (1985).PubMedGoogle Scholar
  16. Nguyen, H., Zhang, S., and Morris, M. E., Effect of flavonoids on MRP1-mediated transport in Panc-1 cells.J. Pharm. Sci., 92, 250–257 (2003).PubMedCrossRefGoogle Scholar
  17. Qian, M., and Gallo, J. M., High-perfomance liquod chromatographic determinination of the calcium channel blocker nimodipine in monkey plasma,J. Chromatogr., 578, 316–320 (1992).PubMedCrossRefGoogle Scholar
  18. Ramsch, K. D., Ahr, G., Tettenborn, D., and Auer, L. M., Overview on pharmacokinetics of nimodipine in healthy volunteer and in patients with subarachnoid hemorrhage,Neurochirurgia., 28, 74078 (1985).Google Scholar
  19. Rocci, M. L. and Jusko, W. J., LAGRAN program for area and moments in pharmacokinetic analysis,Computer Programs in Biomedicine, 16, 203–209 (1983).PubMedCrossRefGoogle Scholar
  20. Saeki, T., Ueda, K., Tanigawara, Y., Hori, R., and Komano, T., P-glycoprotein-mediated transcellular transport of MDR-reversing agents.FEBS Lett., 324, 99–102 (1993).PubMedCrossRefGoogle Scholar
  21. Scherling, D., Buhner, K., Krause, H. P., Karl, W., and Wunsche, C., Biotransformation of nimodipine in rat, dog and monkey,Arzneimittelforschung., 41, 392–398 (1991).PubMedGoogle Scholar
  22. Scholz, H., Pharmacological aspects of calcium channel blockers.Cardiovasc. Drugs Ther., 10, 869–872 (1997).PubMedCrossRefGoogle Scholar
  23. Suwelack, D., Weber, H., and Maruhn, D., Pharmacokinetics of nimodipine, communication: absorption, concentration in plasma and excretion after single administration of [14C] nimodipine in rat, dog and monkey,Arzneimittelforschung., 35, 1787–1794 (1985).PubMedGoogle Scholar
  24. Wacher, V. H., Silverman, J. A., Zhang, Y., and Benet, L. Z., Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics.J. Pharm. Sci., 87, 1322–1330 (1998).PubMedCrossRefGoogle Scholar
  25. Wacher, V. J., Salphati, L., and Benet, L. Z., Active secretion and enterocytic drug metabolism barriers to drug absorption.Adv. Drug Deliv. Rev., 46, 89–102 (2001).PubMedCrossRefGoogle Scholar
  26. Watkins, P. B., The barrier function of CYP3A4 and P-glycoprotein in the small bowel.Adv. Drug Deliv. Rev., 27, 161–170 (1996).CrossRefGoogle Scholar
  27. Zhang, S. and Morris, M. E., Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport.J. Pharmacol. Exp. Ther., 304, 1258–1267 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2006

Authors and Affiliations

  1. 1.College of PharmacyChosun UniversityGwangjuKorea
  2. 2.Chosun Nursing CollegeGwangjuKorea

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