effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats

  • Soon-Pyo Hong
  • Kyoung-Sig Chang
  • Dong-Hyun Choi
  • Jun-Shik Choi
Articles Drug Efficacy

Abstract

The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg-kg-1) to rats pretreated with atorvastatin (0.5 or 2.0 mg-kg-1). Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly (p<0.05, 0.5 mg-kg-1; p<0.01, 2.0 mg-kg-1) increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with 0.5 mgkg-1 atorvastatin, and 1.77-fold in rats pretreated with 2.0 mgkg-1 atorvastatin. Consequently, absolute bio-availability values of diltiazem pretreated with atorvastatin (8.4-10.6%) were significantly higher (p< 0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p<0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (MR.) in the presence of atorvastatin (0.5 or 2.0 mgkg1) was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.

Key words

Diltiazem Desacetyldiltiazem Atorvastatin Pharmacokinetics Rat 

References

  1. Benet, L. Z., Cummins, C. L., and Wu, C. Y., Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data.Curr. Drug Metab., 4, 393–398 (2003).PubMedCrossRefGoogle Scholar
  2. Bogman, K., Peyer, A. K., Torok, M., Kusters, E., and Drewe, J., HMG-CoA reductase inhibitors and P-glycoprotein modulation.Br. J. Pharmacol., 132, 1183–1192 (2001).PubMedCrossRefGoogle Scholar
  3. Boyd, R. A., Stern, R. H., Stewart, B. H., Wu, X., Reyner, E. L., Zegarac, E. A., Randinitis, E. J., and Whitfield, L., Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.J. Clin. Pharmacol., 40, 91–98 (2000).PubMedCrossRefGoogle Scholar
  4. Buckley, M. M-T., Grant, S. M., Goa, K. L., McTabish, D., and Sorkin, E. M., Diltiazem: A reappraisal of its pharmacological properties and therapeutic use.Drugs, 39, 757–806 (1990).PubMedCrossRefGoogle Scholar
  5. Chaffman, M. and Brogden., R. N., Diltiazem: a review of its pharmacological properties and therapeutic efficacy.Drugs, 29, 387–454 (1985).PubMedCrossRefGoogle Scholar
  6. 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).PubMedCrossRefGoogle Scholar
  7. 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, 344–349 (1996).PubMedGoogle Scholar
  8. Goebel, K. J. and Kolle, E. U., High performance liquid chroma-tographic determination of diltiazem and four of its metabolites in plasma.J. Chromatogr, 345, 355–363 (1985).PubMedCrossRefGoogle Scholar
  9. Gottesman, M. M. and Pastan, I., Biochemistry of multidrug resistance mediated by the multidrug transporter.Annu. Rev. Biochem., 62, 385–427 (1993).PubMedCrossRefGoogle Scholar
  10. 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, 1722–1726 (1995a).PubMedCrossRefGoogle Scholar
  11. 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, 609–614 (1995b).PubMedCrossRefGoogle Scholar
  12. 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
  13. Kantola, T., Kivisto, K. T.., and Neuvonen, P. J., Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations.Clin. Pharmacol. Ther., 64, 177–82 (1998a).PubMedCrossRefGoogle Scholar
  14. Kantola, T., Krivisto, K. T., and Nenvonen, P. J., Effect of itraconazole on the pharmacokinetics of atorvastatin.Clin. Pharmacol. Ther., 64, 58–65 (1998b)PubMedCrossRefGoogle Scholar
  15. Kolars, J. C., Schmiedlin-Ren, P., Dobbins, W. O., Schuetz, J., Wrighton, S. A., and Watkins. P. B., Heterogeneity of cytochrome P450IIIA expression in rat gut epithelia.Gastroenterology, 102, 1186–1198 (1992).PubMedGoogle Scholar
  16. Lea, A. P. and McTavish, D., Atorvastatin: a review of its pharmacology and therapeutic potential in the management of hyperlipidaemias.Drugs, 53, 828–847 (1997)PubMedCrossRefGoogle Scholar
  17. Lee, Y. H., Lee, M. H., and Shim, C. K., Pharmacokinetics of diltiazem and deacetyldiltiazem in rats.Int. J. Pharm., 76, 71–76 (1991).CrossRefGoogle Scholar
  18. Lefebvre, M., Homsy, W., Caille, G., and du Souich, P., First-pass metabolism of diltiazem in anesthetized rabbits: role of extrahepatic organs.Pharm. Res., 13, 124–128 (1996).PubMedCrossRefGoogle Scholar
  19. Lennernas, H., Clinical pharmacokinetics of atorvastatin.Clin. Pharmacokinet, 42, 1141–1160 (2003)PubMedCrossRefGoogle Scholar
  20. Lilja, J. J., Kivisto, K. T., and Neuvonen, P. J., Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.Clin. Pharmacol. The., 66, 118–127 (1999)Google Scholar
  21. Me Donnell, C. G., Harte, S., O’Driscoll, J., O’Loughlin, C., Van Pelt, F. N., and Shorten, G. D., The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam. Anaesthesia, 58, 899–904 (2003).CrossRefGoogle Scholar
  22. Mousa, O., Brater, D. C., Sunblad, K. J., and Hall, S. The interaction of diltiazem with simvastatin.Clin. Pharmacol. Ther., 67, 267–274 (2000).PubMedCrossRefGoogle Scholar
  23. Narita, H., Otsuka, M., Yabana, H., and Nagao, T., Hypotensive response of spontaneously hypertensive rats to centrally administered diltiazem and its metabolites: in relevance to the hypotensive action by oral administration.J. Pharma-cobiodyn., 9, 547–53 (1986).Google Scholar
  24. Pichard, L., Gillet, G., Fabre, I., Dalet-Beluche, I., Bonfils, C., Thenot, J. P., and Maurel, P., Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem.Drug Metab. Dispos., 18, 711–719 (1990).PubMedGoogle Scholar
  25. Renders, L., Mayer-Kadner, I., Koch, C., Scharffe, S., Burkhardt, K., Veelken, R., Schmieder, R. E., and Hauser, I. A., Efficacy and drug interactions of the new HMG-CoA reductase inhibitors cerivastatin and atorvastatin in CsA-treated renal transplant recipients. Nephrol. Dial. Transplant., 16, 141–146 (2001).PubMedCrossRefGoogle Scholar
  26. Rocci, M. L. and Jusko, W. J., LAGRAN program for area and moments in pharmacokinetic analysis.Computer Programs in Biomedicine, 16, 203 (1983).PubMedCrossRefGoogle Scholar
  27. 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
  28. Siedlik, P. H., Olson, S. C., Yang, B. B., and Stern, R. H., Erythromycin coadministration increases plasma atorvastatin concentrations.J. Clin. Pharmacol., 39, 501–504 (1999).PubMedGoogle Scholar
  29. 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
  30. Wacher, V. J., Salphati, L., and Benet, L. Z., Active secretion and enterocytic drug metabolism barriers to drug absorption.Adv. DrugDeliv. Rev., 46, 89–102 (2001).CrossRefGoogle Scholar
  31. Wang, E., Casciano, C. N., Clement, R. P., Johnson, and W. W., HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein.Pharm. Res., 18, 800–806 (2001).PubMedCrossRefGoogle Scholar
  32. 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, 1029–1036 (1987).PubMedCrossRefGoogle Scholar
  33. Weir, M. R., Diltiazem: ten years of clinical experience in the treatment of hypertension.J. Clin. Pharmacol., 35, 220–232 (1995).PubMedGoogle Scholar
  34. Wu, X., Whitheld, L. R., and Stewart, B. H., Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and proton-monocarboxylic acid co-transporter.Pharm. Res., 17, 209–215 (2000)PubMedCrossRefGoogle Scholar
  35. Yeung, P. K. Prescott, C., Haddad, C., Montague, T. J., McGregor, C., Quilliam, M. A., Xei, M., Li, R., Farmer, P., and Klassen, G. A., Pharmacokinetics and metabolism of diltiazem in healthy males and females following a single oral dose.Eur. J. Drug Metab. Pharmacokinet, 18, 199–206 (1993).PubMedGoogle Scholar
  36. Yeung, P. K., Feng, J. D. Z., and Buckle, Y. S. J., Pharmacokinetics and hypotensive effect of diltiazem in rabbits: Comparison of diltiazem with its major metabolites.J, Pharm, Pharmacol., 50, 1247–1253 (1998).Google Scholar
  37. Yusa, K. and Tsuruo, T., Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells.Cancer Res., 49, 5002–5006 (1989).PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2007

Authors and Affiliations

  • Soon-Pyo Hong
    • 1
  • Kyoung-Sig Chang
    • 1
  • Dong-Hyun Choi
    • 1
  • Jun-Shik Choi
    • 2
  1. 1.College of MedicineKorea
  2. 2.College of PharmacyChosun UniversityGwangjuKorea

Personalised recommendations