Abstract
Aim:
To evaluate the effects of cyclosporin A and itraconazole, which were used as inhibitors of P-glycoprotein (P-gp) and/or cytochrome P450 (CYP) 3A4 on the pharmacokinetics of atorvastatin in rats.
Methods:
The pharmacokinetic parameters of atorvastatin were measured after intravenous (2 mg/kg) and intra-gastric (10 mg/kg) administration of atorvastatin in rats, which were pretreated with cyclosporin A (5, 10, and 20 mg/kg) or itraconazole (5, 10, and 20 mg/kg).
Results:
Compared with the control rats, cyclosporin A and itraconazole altered the pharmacokinetics of atorvastatin significantly. The AUC0-t values of atorvastatin after intragastric administration, pretreated with cyclosporin A (5–20 mg/kg), increased by 32.3%, 61.8%, and 187.2%, respectively, but the CLbile values decreased (P<0.01, 5–20 mg/kg). With pretreatment of itraconazole (5–20 mg/kg), the AUC0-t values of atorvastatin increased by 88.2%, 102%, and 123%, respectively, but the CLbile values decreased (P<0.01, 5–20 mg/kg).
Conclusion:
These data indicated that cyclosporin A could be effective in inhibiting the efflux of atorvastatin, and itraconazole could be effective in inhibiting both the metabolism and biliary excretion of atorvastatin.
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References
Zager RA . Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int 1996; 49: 314–26.
Ohno Y, Hisaka A, Suzuki H . General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs. Clin Pharma-cokinet 2007; 46: 681–96.
Gumprecht J, Zychma M, Grzeszczak W, Kuźniewicz R, Burak W, Zywiec J, et al. Simvastatin-induced rhabdomyolysis in a CsA-treated renal transplant recipient. Med Sci Monit 2003; 9: CS89–91.
Kantola T, Kivistö KT, Neuvonen PJ . Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58–65.
Neuvonen PJ, Kantola T, Kivistö KT . Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–41.
Neuvonen PJ, Jalava KM . Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60: 54–61.
Lennem PS H, Fager G . Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Clin Pharmacokinet 1997; 32: 403–25.
Smith PF, Eydelloth RS, Grossman SJ, Stubbs RJ, Schwartz MS, Germershausen JI, et al. HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies. J Pharmacol Exp Ther 1991; 257: 1225–35.
Ishigami M, Kawabata K, Takasaki W, Ikeda T, Komai T, Ito K, et al. Drug interaction between simvastatin and itraconazole in male and female rats. Drug Metab Dispos 2001; 29: 1068–72.
Wierzbicki AS . Atorvastatin. Expert Opin Pharmacother 2001; 2: 819–30.
Black A E, Sinz MW, Hayes RN, Woolf TF . Metabolism and excretion studies in mouse after single and multiple oral doses of the-3-Hydroxy-3-Methyl glutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos 1998; 26: 755–63.
Kantola T, Krivisto KT, Nenvonen PJ . Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58–65.
Wu X, Whitheld LR, Stewart BH . Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and proton-mono-carboxylic acid co-transporter. Pharm Res 2000; 17: 209–15.
Berruet N, Sentenac S, Auchere D, Gimenez F, Farinotti R, Fernandez C . Effect of efavirenz on intestinal p-glycoprotein and hepatic p450 function in rats. J Pharm Pharmaceut Sci 2005; 8: 226–34.
Kageyama M, Namiki H, Fukushima H, Ito Y, Shibata N, Takada K . In vivo effects of cyclosporin A and ketoconazole on the pharmacokinetics of representative substrates for P-glycoprotein and cytochrome P450 (CYP) 3A in rats. Biol Pharm Bull 2005; 28: 316–22.
Ma L, Dong J, Chen XJ . Development and validation of atorvastatin by LC-ESI-MS and application in bioequivalence research in healthy Chinese volunteers. Chromatographia 2007; 65: 737–41.
Tsuji A, Terasaki T, Takabatake Y, Tenda Y, Tamai I, Yamashima T, et al. P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci 1992; 51: 1427–37.
Terao T, Hisanaga E, Sai Y, Tamai I, Tsuji A . Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier. J Pharm Pharmacol 1996; 48: 1083–9.
Lau YY, Okochi H, Huang Y, Benet LZ . Pharmacokinetics of atorvastatin and its hydroxyl metabolites in rats and the effects of concomitant rifampicin single doses: relevance of First-pass effect from hepatic uptake transporters, and intestinal and hepatic metabolism. Drug Metab Dispos 2006; 34: 1175–81.
Neuvonen PJ, Niemi M, Backman JT . Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006; 80: 565–81.
Saito M, Hirata-Koizumi M, Miyake S, Hasegawa R . Withdrawal of cerivastatin revealed a flaw of post-marketing surveillance system in the United States. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku 2005; 123: 41–5.
Dresser GK, Spence JD, Bailey DG . Pharmacokinetic-pharmacody-namic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 41–57.
Williams D, Feely J . Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002; 415: 343–70.
Jacobson TA . Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94: 1140–6.
Molden E, Asberg A . Metabolic interactions with statins. Tidsskr Nor Laegeforen 2001; 121: 189–93.
Igel M, Sudhop T, von Bergmann K . Metabolism and drug interactions of 3-hydroxyl-3-methylglutaryl coenzyme A-reductase inhibitors (statins). Eur J Clin Pharmacol 2001; 57: 357–64.
Maltz HC, Balog DL, Cheigh JS . Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother 1999; 33: 1176–9.
Hermann M, Asberg A, Christensen H, Holdaas H, Hartmann A, Reu-bsaet JL . Substantially elevated levels of atorvastatin and metabolites in cyclosporine-treated renal transplant recipients. Clin Pharmacol Ther 2004; 76: 388–91.
Launay-Vacher V, Izzedine H, Deray G . Statins' dosage in patients with renal failure and cyclosporine drug-drug interactions in transplant recipient patients. Int J Cardiol 2005; 101: 9–17.
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The research was funded by National Natural Science Foundation of China (No 30472060).
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Dong, J., Yu, X., Wang, L. et al. Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats. Acta Pharmacol Sin 29, 1247–1252 (2008). https://doi.org/10.1111/j.1745-7254.2008.00858.x
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DOI: https://doi.org/10.1111/j.1745-7254.2008.00858.x
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