YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Effect of Naringin on the Bioavailability of Losartan in Rats

흰쥐에서 나린진이 로살탄의 생체이용율에 미치는 영향

  • Received : 2009.04.23
  • Accepted : 2009.07.21
  • Published : 2009.10.31
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Abstract

The present study was to investigate the effect of naringin, a flavonoid, on the pharmacokinetics of losartan in rats. Pharmacokinetic parameters of losartan in rats were determined after an oral administration of losartan (9 mg/kg) in the presence or absence of naringin (0.5, 2.5 and 10 mg/kg). The pharmacokinetic parameters of losartan were significantly altered by the presence of naringin compared with the control group (given losartan alone). Presence of naringin significantly (p<0.05, 2.5 mg/kg; p<0.01, 10 mg/kg) increased the area under the plasma concentration?time curve (AUC) of losartan by 43.7~63.0% and peak plasma concentration ($C_{max}$) of losartan by 31.7~45.5%. Consequently, the absolute bioavailability (AB) of losartan in the presence of naringin was 43.8~62.9%, which was enhanced significantly (p<0.05, p<0.01) compared to that in the oral control group (22.4%). The relative bioavailability (R.B.) of losartan increased by 1.44- to 1.63-fold in the presence of naringin. However, there was no significant change in the peak plasma concentration ($T_{max}$) and terminal half-life ($t_{1/2}$) of losartan in the presence of naringin. In conclusion, the presence of naringin significantly enhanced the oral bioavailability of losartan, implying that presence of naringin might be mainly effective to inhibit the cytochrome P450 (CYP)3A-mediated metabolism, resulting in reducing gastrointestinal and hepatic first-pass metabilism and Pglycoprotein (P-gp)-mediated efflux of losartan in small intestine. Concurrent use of naringin or naringin-containing dietary supplement with losartan should require close monitoring for potential drug interactions.

Keywords

References

  1. Javier, D. : Review of the molecular pharmacology of losartan and its possiblerelevance to stroke prevention in patients with hypertension. Clinical Therapeutics. 28, 832 (2006) https://doi.org/10.1016/j.clinthera.2006.06.002
  2. McIntyre, M., Caffe, S. E., Michalak, R. A. and Reid, J. L. : Losartan, an orally active angiotensin (AT1) receptor antagonist: a review of its efficacy and safety in essential hypertension. Pharmacol. Ther. 74, 181 (1997) https://doi.org/10.1016/S0163-7258(97)82002-5
  3. Inagami, T., Iwai, N., Sasaki, K., Yamamo, Y., Bardhan, S., Chaki, S., Guo, D. F. and Furuta, H. : Cloning, expression and regulation of angiotensin II receptors. J. Hypertens. 8, 713 (1992)
  4. Lo, M. W., Goldberg, M. R., McCrea, J. B., Lu, H., Furtek, C. I. and Bjornsson, T. D. : Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP-3174 in humans. Clin. Pharmacol. Ther. 58, 641 (1995) https://doi.org/10.1016/0009-9236(95)90020-9
  5. Soldner, A., Hildegard, S. L. and Mutschler, E. : HPLC assays to simultaneously determine the angiotensin-AT1 antagonist losartan as well as its main and active metabolite EXP-3174 in biological material of humans and rats. Journal of Pharmaceutical and Biomedical Analysis. 16, 863 (1998) https://doi.org/10.1016/S0731-7085(97)00128-3
  6. Soldner, A., Christians, U., Susanto, M., Wacher, V. J., Silverman, J. A. and Benet, L. Z. : Grapefruit juice activates Pglycoprotein-mediated drug transport. Pharm. Res. 16, 478 (1999) https://doi.org/10.1023/A:1011902625609
  7. Stearns, R. A., Chakravarty, P. K., Chen, R. and Chiu, S. H. : Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metab. Dispos. 23, 207 (1995)
  8. Stearns, R. A., Miller, R. R., Doss, G. A., Chakravarty, P. K., Rosegay, A., Gatto, G. J. and Chiu, S. H. : The metabolism of DuP 753, a nonpeptide angiotensin II receptor antagonist, by rat, monkey, and human liver slices. Drug. Metab. Dispos. 20, 281 (1992)
  9. Yun, C. H., Lee, H. S., Lee, H., Rho, J. K., Jeong, H. G. and Guengerich, F. P. : Oxidation of the angiotensin II receptor antagonist losartan (DuP 753) in human liver microsomes. Role of cytochrome P4503A(4) in formation of the active metabolite EXP3174. Drug. Metab. Dispos. 23, 285 (1995)
  10. Meadowcroft, A. M., Williamson, K. M., Patterson, J. H., Hinderliter, A. L. and Pieper, J. A. : The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers. J. Clin. Pharmacol. 39, 418 (1999) https://doi.org/10.1177/00912709922007886
  11. Kaukonen, K. M., Olkkola, K. T. and Neuvonen, P. J. : Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur. J. Clin. Pharmacol. 53, 445 (1998) https://doi.org/10.1007/s002280050405
  12. McCrea, J. B., Cribb, A., Rushmore, T., Osborne, B., Gillen, L., Lo, M. W., Waldman, S., Bjornsson, T., Spielberg, S. and Goldberg, M. R. : Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E-3174. Clin. Pharmacol. Ther. 65, 348 (1999) https://doi.org/10.1016/S0009-9236(99)70114-1
  13. 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 (2001) https://doi.org/10.1016/S0169-409X(00)00126-5
  14. 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
  15. Gan, L. S. L., Moseley, M. A., Khosla, B., Augustijns, P. F., Bradshaw, T. P., Hendren, R. W. and Thakker, D. R. : CYP3ALike 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 (1996)
  16. 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 (1998) https://doi.org/10.1021/js980082d
  17. Ito, K., Kusuhara, H. and Sugiyama, Y. : Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption theoretical approach. Pharm. Res. 16, 225 (1999) https://doi.org/10.1023/A:1018872207437
  18. 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
  19. Gan, L.-S. 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 (1996)
  20. Watkins, P. B. : The barrier function of CYP3A4 and Pglycoprotein in the small bowel. Adv. Drug. Deliv. Rev. 27, 161 (1996) https://doi.org/10.1016/S0169-409X(97)00041-0
  21. 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 (1998) https://doi.org/10.1021/js980082d
  22. Ito, K., Kusuhara, H. and Sugiyama, Y. : Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption theoretical approach. Pharm. Res. 16, 225 (1999) https://doi.org/10.1023/A:1018872207437
  23. Reynolds, J. E. F. : Martindale - The extra pharmacopeia. Pharmaceutical Press. London (1993)
  24. 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
  25. 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 (2001)
  26. 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
  27. 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
  28. 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
  29. 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)
  30. The Merck Index, 12th Edition, Merck and Co. Inc., Rahway, USA. pp. 6512 (1996)
  31. 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
  32. 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
  33. 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 (1999) https://doi.org/10.1046/j.1365-2125.1999.00052.x
  34. 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 (2001)
  35. 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 (2000)
  36. Choi, J. S. and Shin, S. C. : Enhanced paclitaxel bioavailability after oral coadministration of paclitaxel prodrug with naringin to rats. Int. J. Pharm. 23, 149 (2005)
  37. Choi, J. S. and Han, H. K. : Enhenced oral exposure of diltiazem by the concomitant use of naringin in rats. Int. J. Pharm. 30, 122 (2005)
  38. Kim, H. J. and Choi, J. S. : Effectof naringin on the pharmacolinetics of verapamil and one of its metabolites, norverapamil, in rabbits. Bio. Drug. Dispos. 26, 295 (2005) https://doi.org/10.1002/bdd.459
  39. Zarghi, A., Foroutan, S. M., Shafaati, A. and Khoddam, A. : A rapid HPLC method for the determination of losartan in human plasma using a monolithic column. Arzneimittelforschung. 55, 569 (2005)