[Incremental effect and mechanism of cyclosporine on blood concentration of statins and statin package insert information in Japan].
Cyclosporine is an indispensable immunosuppressant used in organ transplant patients, who frequently manifest hyperlipidemia. Statins, which are cholesterol-lowering agents, are often combined with cyclosporine in the treatment of hyperlipidemia of organ transplant patients. Since cyclosporine is a substrate and inhibitor of CYP3A4, researchers suspect that the immunosuppressant inhibits CYP3A4-mediated metabolism of statins, leading to an increase in statin plasma concentration and infrequently resulting in rhabdomyolysis. However, a number of clinical trials have shown cyclosporine to increase the plasma concentration of all developed statins, including those not metabolized by CYP3A4. Furthemore, recent mechanistic studies have shown organic anion transporting peptides (OATP) C to mediate the uptake of some statins and cyclosporine has been shown to inhibit the uptake via OATP-C in cultured cells. Therefore, the inhibition of hepatic uptake of statins is considered to be one of the mechanisms by which cyclosporine incrementally increases statin blood concentration. However, most current Japanese package inserts of statins give no information on change in pharmacokinetic parameters such as AUC and Cmax in the combined medication with cyclosporine. Furthermore, in the Japanese package inserts, it is either stated that cyclosporine inhibits CYP3A4-mediated metabolism or no comment is made on the mechanism. The package insert should properly provide available quantitative information on the change of pharmacokinetic parameters and the probable mechanism of action.