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

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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.

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References

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Chaffman, M. and Brogden., R. N., Diltiazem: a review of its pharmacological properties and therapeutic efficacy.Drugs, 29, 387–454 (1985).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Gottesman, M. M. and Pastan, I., Biochemistry of multidrug resistance mediated by the multidrug transporter.Annu. Rev. Biochem., 62, 385–427 (1993).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Kantola, T., Krivisto, K. T., and Nenvonen, P. J., Effect of itraconazole on the pharmacokinetics of atorvastatin.Clin. Pharmacol. Ther., 64, 58–65 (1998b)

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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)

    Article  PubMed  CAS  Google Scholar 

  • Lee, Y. H., Lee, M. H., and Shim, C. K., Pharmacokinetics of diltiazem and deacetyldiltiazem in rats.Int. J. Pharm., 76, 71–76 (1991).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Lennernas, H., Clinical pharmacokinetics of atorvastatin.Clin. Pharmacokinet, 42, 1141–1160 (2003)

    Article  PubMed  Google Scholar 

  • 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)

    CAS  Google Scholar 

  • 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).

    Article  Google Scholar 

  • Mousa, O., Brater, D. C., Sunblad, K. J., and Hall, S. The interaction of diltiazem with simvastatin.Clin. Pharmacol. Ther., 67, 267–274 (2000).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Rocci, M. L. and Jusko, W. J., LAGRAN program for area and moments in pharmacokinetic analysis.Computer Programs in Biomedicine, 16, 203 (1983).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Weir, M. R., Diltiazem: ten years of clinical experience in the treatment of hypertension.J. Clin. Pharmacol., 35, 220–232 (1995).

    PubMed  CAS  Google Scholar 

  • 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)

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. College of Medicine, Korea

    Soon-Pyo Hong, Kyoung-Sig Chang & Dong-Hyun Choi

  2. College of Pharmacy, Chosun University, 501-759, Gwangju, Korea

    Jun-Shik Choi

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  1. Soon-Pyo Hong
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  2. Kyoung-Sig Chang
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Correspondence to Jun-Shik Choi.

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Hong, SP., Chang, KS., Choi, DH. et al. effect of atorvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. Arch Pharm Res 30, 90–95 (2007). https://doi.org/10.1007/BF02977783

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