YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Effect of Pretreatment of Naringin on the Bioavailability of Diltiazem and Deacetyldiltiazem in Rabbits

토끼에서 나린진이 틸티아젬과 그대사체, 디아세틸딜티아젬의 생체이용율에 미치는 영향

  • Published : 2005.06.01
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Abstract

The purpose of this study was to investigate the effect of naringin pretreatment on the bioavailability and phar-macokinetics of diltiazem and one of its metabolites, deacetyldiltiazem, in rabbits. Pharmacokinetic parameters of diltiazem and deacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) pretreated with naringin (1.5, 7.5 and 15 mg/kg). Absorption rate constant ($k_a$) of diltiazem after oral administration of diltiazem pretreated with naringin was significantly (p<0.05 or p<0.0l) increased compared to the control group. Area under the plasma concentration-time curve (AUC) and peak concentration ($C_{max}$) of the diltiazem were significantly (p<0.05 or p<0.01) higher than those of the control. Absolute bioavailability ($AB\%$) of diltiazem pretreated with naringin ranged from $13.5\%$ to $18.6\%$, being enhanced compared to that of the control, $7.2\%$. Relative bioavailability ($RB\%$) of diltiazem was $1.9\~2.6$ times higher than that of the control group. There was no significant change in terminal half-life ($t_{1/2}$) and $T_{max}$ of diltiazem in the presence of naringin. AUC of deacetyldiltiazem pretreated with naringin was significantly (p<0.05) higher than (p<0.05) that of the control. But the metabolite ratios (MR) were significantly decreased (p<0.05), implying that pretreatment of naringin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. In this study, pretreatment of naringin significantly enhanced the oral bioavailability of diltiazem. These results suggested that the diltiazem dosage should be adjusted when it is administered with naringin or a naringin-containing dietary supplement in the clinical setting.

Keywords

References

  1. AHFS Drug Information, AFS 1317 (1988)
  2. Scholz, H. : Pharmacological aspects of calcium channel blockers. Cardiovas. Drugs Ther. 10, 869 (1997) https://doi.org/10.1007/BF00051613
  3. Epstein, M. and Loutzenhister, R. D. : Effects of calcium antagonists on renal hemodynamics. Am. J. Kidney Dis. 16, 10 (1990)
  4. Ruilope, L. M. and Alcaar,J. M. : Renal effects of calcium entry blockers. Cardiovas. Drugs Ther. 4, 979 (1990) https://doi.org/10.1007/BF02018304
  5. Sterzel, P. B. : Renal actions of calcium antagonists.J. Cardiovas. Pharmacol. 10, 17 (1987) https://doi.org/10.1097/00005344-198706107-00004
  6. Eichelbaum, M. and Echizen, H. : Clinical pharmacology of calcium antagonists: A critical review.J. Cardiovas. Pharmacol. 6, 963 (1984) https://doi.org/10.1097/00005344-198400067-00006
  7. Bianchetti, G., Regazzi, M., Rondanelli, R., Ascalone, V. and Morselli, P. L. : Bioavailability of diltiazem as a function of the administered dose. Biopharm. Drug Dispos. 12, 391 (1991) https://doi.org/10.1002/bdd.2510120508
  8. Klaassen, C. D. Toxicology. 5th ed. New York: McGraw-Hill. 113 (1999)
  9. Watkins, P. B., Wrighton, S. A., Schuetz, E. G., Molowa, D. T. and Guzelian, P. S. : Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J. Clin. Invest. 80, 1029 (1987) https://doi.org/10.1172/JCI113156
  10. Kolars, J. C., Schmiedlin-Ren, P., Dobbins, W. O., 3rd, Schuetz, J., Wrighton, S. A. and Watkins, P. B. : Heterogeneity of cytochrome P450IIIA expression in rat gut epithelia. Gastroenterology 102, 1186 (1992) https://doi.org/10.1016/0016-5085(92)90756-O
  11. Lefebvre, M., Homsy, W., Caille, G. and du Souich, P. : Firstpass metabolism of diltiazem in anesthetized rabbits: Role of extrahepatic organs. Pharm. Res. 13, 124 (1996) https://doi.org/10.1023/A:1016042220817
  12. Homsy, W., Caille. G. and du Souich, P. : The site of absorption in the small intestine determines diltiazem bioavailability in the rabbit. Pharm. Res. 12, 1722 (1995) https://doi.org/10.1023/A:1016217822770
  13. Homsy, W., Lefebvre, M., Caille, G. and du Souich, P. : Metabolism of diltiazem in hepatic and extrahepatic tissues of rabbits: In vitro studies. Pharm. Res. 12, 609 (1995) https://doi.org/10.1023/A:1016226601988
  14. Yusa, K. and Tsuruo, T. : Reversal mechanism of multidrug resistance by verapamil: Direct binding of verapamil to Pglycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells. Cancer Res. 49, 5002 (1989)
  15. Saeki, T., Ueda, K., Tanigawara, Y., Hori, R. and Komano, T. : P-glycoprotein-mediated transcellular transport of MDR-reversing agents. FEBS Lett. 324, 99 (1993) https://doi.org/10.1016/0014-5793(93)81540-G
  16. Chaudhary, P. M. and Robinson, I. B. : Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66, 85 (1991) https://doi.org/10.1016/0092-8674(91)90141-K
  17. Van Asperen, J., Van Tellingen, O., Sparreboom, A., Schinkel, A. H., Borst, P., Nooijen, W. J. and Beijnen, J. H. : Enhanced oral bilavailability of diltiazem in mice treated with the p-glycoprotein blocker SDZ PSC 833. Br. J. Cancer 76, 1181 (1997) https://doi.org/10.1038/bjc.1997.530
  18. Biedler, J. L. and Riehm, H. : Cellular resistance to actinomycin D in Chinese hamster cells in vitro: crossresistance, radioautographic, and cytogenetic studies. Cancer Res. 30, 1174 (1970)
  19. Ford, J. M. : Modulators of multidrug resistancepreclinical studies. Hematol. Oncol. Clin. N. Am. 9, 337 (1995)
  20. Fruehauf, J. P. and Manetta, A. : Use of extreme drug resistance assay to evaluate mechanisms of resistance in ovarian cancer: Taxol resistance and MDRI expression. Contrib. Gynecol. Obstet. 19, 39 (1994)
  21. Dixon, R. A. and Steele, C. : Flavonoids and isoflavonoids-gold mine for metabolic engineering. Trends Plant Sci. 4, 394 (1999) https://doi.org/10.1016/S1360-1385(99)01471-5
  22. Nijveldt, R. J., van Nood, E., van Hoom, D. E. C., Boelens, P. G., van Norren, K. and van Leeuwen, PAM. : Flavonoids: A review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr. 74, 418 (2001)
  23. Doostdar, H., Burke, M. D. and Mayer, R. T. : Bioflavonoids: Selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1. Toxicology 144, 31 (2000) https://doi.org/10.1016/S0300-483X(99)00215-2
  24. Hodek, P., Trefil, P. and Stiborova, M. : Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem. Biol. Interact. 139, 1 (2002) https://doi.org/10.1016/S0009-2797(01)00285-X
  25. Dupuy, J., Larrieu, G., Sutra, J. F., Lespine, A. and Alvinerie, M. : Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: Quercetin. Vet. Parasitol. 112, 337 (2003) https://doi.org/10.1016/S0304-4017(03)00008-6
  26. 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 (2000)
  27. The Merck Index, 12th Edition, Merck and Company., Rahway, USA. 6512 (1996)
  28. Kim, D. H., Jung, E. A., Sohng, I. S., Han, J. A., Kim, T. H. and Han, M. J. : Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch. Pharm. Res. 21, 17 (1998) https://doi.org/10.1007/BF03216747
  29. Zhang, H., Wong, C. W., Coville, P. G. and Wanwimolruk, S. : Effect of the grapefruit flavonoid naringin on pharmacokinetics of quinine in rats. Drug Meta. Drug Interact. 17, 351 (2000)
  30. Ho, P. C., Saville, D. J. and Wanwimolruk, S. : Inhibition of human CYF 3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J. Pharm. Pharm. Sci. 4, 217 (2001)
  31. Takanaga, H., Ohnishi, A., Matsuo, H. and Sawada, Y. : Inhibition of vinblastine efflux mediated by P-glycoprotein by grapefruit juice components in caco-2 cells. Biol. Pharm. Bull. 21, 1062 (1998) https://doi.org/10.1248/bpb.21.1062
  32. Eagling, V. A., Profit, L. and Back, D. J. : Inhibition of the CYF 3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br. J. Clin. Pharmacol. 48, 543 (1999) https://doi.org/10.1046/j.1365-2125.1999.00052.x
  33. Goebel, K. J. and Kolle, E. U. : High performance liquid chromatographic dertermination of diltiazem and four of its metabolites in plasma. J. Chromatogr. 345, 355 (1985) https://doi.org/10.1016/0378-4347(85)80172-9
  34. Hermann, P. H., Rodger, S. D., Remones, G., Thenot, J. P., London, D. R. and Morselli, P. L. : Pharmacokinetics of diltiazem after intravenous and oral administration. Eur. J. Clin. Pharmacol. 24, 349 (1983) https://doi.org/10.1007/BF00610053
  35. Yeung, P. K., Mosher, S. J., Quilliam, M. A. and Montague, T. J. : Species comparison of pharmacokinetics and metabolism of diltiazem in humans, dogs, rabbits and rats. Drug Metab. Dispos. 18, 1055 (1990)
  36. Rocci, M. L. and Jusko, W. J. : LAGRAN program for area and moments in pharmacokinetic analysis. Computer Programs in Biomedicine. 16, 203 (1983) https://doi.org/10.1016/0010-468X(83)90082-X
  37. Gottesman, M. M. and Pastan, I. : Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385 (1993) https://doi.org/10.1146/annurev.bi.62.070193.002125
  38. Ito, K., Kusuhara, H. and Sugiyama, Y. : Effects of intestinal CYP 3A4 and P-glycoprotein on oral drug absorption-theoretical approach. Pharm. Res. 16, 225 (1999) https://doi.org/10.1023/A:1018872207437