Effect of Naringin Pretreatment on Bioavailability of Verapamil in Rabbits

  • Published : 2006.01.01

Abstract

The aim of present study is to investigate the effect of naringin on the pharmacokinetics of verapamil and its major metabolite, norverapamil in rabbits. The pharmacokinetic parameters of verapamil and norverapamil were determined after administering verapamil (9 mg/kg) orally to rabbits in the pretreated with naringin (1.5, 7.5, and 15 mg/kg). Naringin pretreatment significantly altered the pharmacokinetic parameters of verapamil. Compared with the control group (given verapamil alone), the $K_a,\;C_{max}$ and AUC of verapamil were significantly (p<0.05 or p<0.01) increased in the pretreatment of naringin, However there were no significant change in $T_{max}\;and\;t_{1/2}$ of verapamil. Consequently, pretreatment of naringin significantly (p<0.05, p<0.01) increased the AB% of verapamil significantly in a dose dependent manner (p<0.05 or p<0.01 ), and elevated the RB% of verapamil by 1.26- to 1.69-fold. the MR of verapamil were significantly (p<0.05) increased in the pretreatment of naringin, implying that pretreatment of naringin may effectively inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of naringin enhanced the oral bioavailability of verapamil. Based on these results, the verapamil dosage should be adjusted when given with naringin or a naringin-containing dietary supplement.

Keywords

References

  1. Ader, P., Wessmann, A., and Wolffram, S., Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radical Biol. Med., 28, 1056-1067 (2000) https://doi.org/10.1016/S0891-5849(00)00195-7
  2. Bardelmeijer, H. A., Beijnen, J. H., Brouwer, K. R., Rosing, H., Nooijen, W. J., Schellens, J. H., and van Tellingen, O., Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. Clin. Cancer Res., 6, 4416-4421 (2000)
  3. Benet, L. Z., Cummins, C. L., and Wu, C. Y., Transporterenzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr. Drug Metab., 4, 393-398 (2003) https://doi.org/10.2174/1389200033489389
  4. Buse, D., Cosme, J. P., Beaune, H. K., and Kroemer, M., Eichelbaum, Cytochromes of the P450 2C subfamily are the major enzymes imvolved in the O-demethylation of verapamil in humans. Naunyn-Schmiedeberg's Arch. Pharmacol., 353, 116-121 (1995)
  5. Cody, V., Plant Flavoniods in Biology and Medicine. Prog. Clin. Biol. Res., 213, 233-239 (1986)
  6. Cody, V., Plant Flavonoids in Biology and Medicine, part II. Prog. Clin. Biol. Res., 280, 111-120 (1988)
  7. Cummins, C. L., Jacobsen, W., and Benet, L. Z., Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther., 300, 1036-1045 (2002) https://doi.org/10.1124/jpet.300.3.1036
  8. Davis, J., Williams, L. S., Hill, D., and Lowenthal, D. T., Effects of fosinopril or sustained-release verapamil on blood pressure and serum techolamine concentrations in elderly hypertensive men. Am. J. Ther., 7, 3-9 (2000) https://doi.org/10.1097/00045391-200007010-00002
  9. Dey, C. S., Varma, M. V., Ashokraj, Y., and Panchagnula, R., Pglycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol. Res., 48, 347- 359 (2003) https://doi.org/10.1016/S1043-6618(03)00158-0
  10. Dixon, R. A. and Steele, C., Flavonoids and isoflavonoids-gold mine for metabolic engineering. Trends Plant Sci., 4, 394-400 (1999) https://doi.org/10.1016/S1360-1385(99)01471-5
  11. Doppenschmitt, S., Spahn-Langguth, H., Regardh, C. G., and Langguth, P., Role of P-glycoprotein-mediated secretion in absorptive drug permeability: An approach using passive membrane permeability and affinity to P-glycoprotein. J. Pharm. Sci., 88, 1067-1072 (1999) https://doi.org/10.1021/js980378j
  12. Doostdar, H., Burke, M. D., and Mayer, R. T., Bioflavoniods: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1. Toxicology, 144, 31-38 (2000) https://doi.org/10.1016/S0300-483X(99)00215-2
  13. Dupuy, J., Larrieu, G., Sutra, J. F., Lespine, A., and Alvinerie, M., Enhancement of moxidectin bioavailability in lamb by a natural flavonoid. Vet. Parasitol., 112, 337-347 (2003) https://doi.org/10.1016/S0304-4017(03)00008-6
  14. Eagling, V. A., Profit, L., and Back, D. J., Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br. J. Clin. Pharmacol., 48, 543- 552 (1999) https://doi.org/10.1046/j.1365-2125.1999.00052.x
  15. Eichelbaum, M., Mikus, G., and Vogelgesang, B., Pharmacokinetics of (+)-,(-)- and (${\pm}$)-verapamil after intravenous administration. Brit. J. Clin. Pharmacol., 17, 453-458 (1984) https://doi.org/10.1111/j.1365-2125.1984.tb02371.x
  16. Eichelbaum, M., Remberg, E. G., Schomerus, M., and Dengler, H. J., The metabolism of D,L(14C) verapamil in man. Drug Metab. Dispos., 7, 145-148 (1979)
  17. Fleckenstein, A., Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann. Rev. Pharmacol. Toxicol., 17, 149-166 (1977) https://doi.org/10.1146/annurev.pa.17.040177.001053
  18. Giacomini, J. C., Nelson, W. L., Theodore, L., Wong, F. M., Rood, D., and Giacomini, M., The pharmacokinetics and pharmacodynamics of d- and dl-verapamil in rabbits. J. Cardiovasc Pharmacol., 7, 469-475 (1985) https://doi.org/10.1097/00005344-198505000-00009
  19. Gould, B. A., Mann, S., Kieso, H., Bala Subramanian, V., and Raftery, E. B., The 24-hour ambulatory blood pressure proflie with verapamil. Circulation, 65, 22-27 (1982) https://doi.org/10.1161/01.CIR.65.1.22
  20. Ho, P. C., Saville, D. J., and Wanwimolruk, S., Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J. Pharm. Pharm. Sci., 4, 217-227 (2001)
  21. 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) https://doi.org/10.1016/S0009-2797(01)00285-X
  22. Kim, H. J. and Choi, J. S., Effects of naringin on the pharmacokinetics of verapamil and one of its metabolites, narverapamil, in rabbits. Biopharm. Drug Dispos., 26, 295- 300 (2005) https://doi.org/10.1002/bdd.459
  23. Kim, D. H., Jung, E. A., Shong, I. S., and Han, J. A., Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch. Pharm. Res., 21, 17-23 (1998) https://doi.org/10.1007/BF03216747
  24. Krecic-Shepard, M. E., Barmas, C. R., and Schwartz, J. B., Faster clearance of sustained release verapamil in men versus women: Continnuing observations on sex specific differences after oral administration of verapamil. Clin. Pharmacol. Ther., 68, 286-292 (2000) https://doi.org/10.1067/mcp.2000.109356
  25. Kroemer, H. K., Gautier, J. C., Beaune, P., Henderson, C., Wolf, C. R., and Eichelbaum, M., Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn- Schmiedeberg's Arch. Pharmacol., 348, 332-337 (1993)
  26. Kumar, G. N., Walle, U. K., and Walle, T., Cytochome P450 3Amediated human liver microsomal taxol 6$\'{a}$-hydroxylation. J. Pharmacol. Exp. Ther., 268, 1160-1165 (1994)
  27. Lewis, G. R., Morley, K. D., Lewis, B. M., and Bones, P. J., The treatment of hypertension with verapamil. NZ Medical J., 87, 351-354 (1978)
  28. Manach, C., Morand, C., Demigne, C., Texier, O., Regerat, F., and Remesy, C., Bioavailability of rutin and quercetin in rats. FEBS Lett., 409, 12-16 (1997) https://doi.org/10.1016/S0014-5793(97)00467-5
  29. Meng, X., Maliakal, P., Lu, H., Lee, M. J., and Yang, C. S., Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J. Agric. Food Chem., 52, 935-942 (2004) https://doi.org/10.1021/jf030582e
  30. Mori, Y., Hanada, K., Mori, T., Tsukahara, Y., Hashiguchi, M., and Ogata, H., Stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil in rabbits. Biol. Pharm. Bull., 24, 806-810 (2001) https://doi.org/10.1248/bpb.24.806
  31. Nijveldt, R. J., van Nood, E., van Hoorn, D. E. C., Boelens, P. G.,van Norren, K., and van Leeuwen, P. A. M., Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr., 74, 418-425 (2001) https://doi.org/10.1093/ajcn/74.4.418
  32. Rahman, A., Korzekwa, K. R., Grogan, J., Gonzalezs, F. J., Harris, J. W., Selective biotransformation of taxol to 6$\alpha$- hydroxytaxol by human cytochrome P450 2C8. Cancer Res., 54, 5543-5546 (1994)
  33. Rocci, M. L. and Jusko, W. J., LAGRAN program for area and moments in pharmacokinetic analysis. Comp. Prog. In. Biomed., 16, 203-209 (1983) https://doi.org/10.1016/0010-468X(83)90082-X
  34. Schomerus, M., Spiegelhaider, B., Stieren, B., and Eichelbaum, M., Physiologic disposition of verapamil in man. Cardiovasc. Res., 10, 605-612 (1976) https://doi.org/10.1093/cvr/10.5.605
  35. Takanaga, H. A., Ohnishi, H., and Matsuo, Y., Sawada, Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in caco-2 cells. Biol. Pharm. Bull., 21, 1062-1066 (1998) https://doi.org/10.1248/bpb.21.1062
  36. Takahama, U., Inhibition of lipoxygenase-dependent lipid peroxidation by quercetin: mechanism of antioxidative function. Phytochemistry, 24, 1443 -1446 (1985) https://doi.org/10.1016/S0031-9422(00)81040-7
  37. Wacher, V. J., Salphati, L., and Benet, L. Z., Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Deliver. Rev., 20, 99-112 (1996) https://doi.org/10.1016/0169-409X(95)00127-S
  38. Zhang, H., Wong, C. W., Coville, P. G., and Wanwimolruk, S., Effect of the grapefruit flavonoid naringin on pharmacokinetics of quinine in rats. Drug Metabol. Drug Interact., 17, 351-363 (2000)