Cyclosporine cerivastatin

Muck, W., Mai, I., Fritsche, L., Ochmann, K., Rohde, G., Unger, S., Johne, A., Bauer, S., Budde, K., Roots, I., Neumayer, H.-H., Kuhlmann, J., Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporin-treated kidney transplant recipients, Clin. Pharmacol. Ther. 1999, 65, 251— 261. 

Muck W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S, Johne A, Bauer S, Budde K, Roots I, Neumayer HH, Kuhlmann J. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999 65(3) 251-61. 

Shitara Y, Itoh T, Sato H, et al. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther 2003 304 610-616. 

In a clinical study, plasma concentrations of the cholesterol-lowering drug cerivastatin were determined after oral administration of a 0.2 mg single dose of cerivastatin to 12 kidney transplant recipients and healthy volunteers [22]. The mean AUC value of cerivastatin (36.2ng/mlh) in the kidney transplant recipients with cyclosporin was approximately fourfold higher than that in healthy volunteers (9.5 ng/mlh) who received the same oral dose of cerivastatin without cyclosporin treatment [22]. Due to the almost complete absorption of cerivastatin after oral administration and the fact that cyclosporin does not affect the elimination half-life, the authors suggested that the increased AUC observed in transplant patients cannot be explained only by cyclosporin-based CYP3A inhibition [23]. 

Shitara. Y.. Hirano. M.. Adachi. Y.. Itoh. T, Sato, H.. and Sugiyama. Y. (2004) fn vitro and in vivo correlation of the inhibitory effect of cyclosporin A on the transporter-mediated hepatic uptake of cerivastatin in rats. Drug Metabolism and Disposition, 32. 1468-1475. 

Cyclosporine increases the systemic exposure of all statins (lovastatin, simvastatin, pravastatin, cerivastatin, and rosuvastatin), due to drug-drug interaction (via either CYPs or transporters like P-gp and OATP) in the liver. Rosuvastatin has been shown to be a substrate for the human liver transporter OATP2 and BCRP, but not P-gp. It s metabolic clearance is low and mainly mediated by CYP2C9. CsA treatment in transplant recipients increased AUCq 2h and Cmax of rosuvastatin (10 mg) by 7.1 and 10.6-fold, respectively, compared with control values, due to CsA inhibition of OATP2-mediated rosuvastatin hepatic uptake (Simonson et al., 2004). 

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