Major
Established
Descrição
Cyclosporine raises simvastatin exposure by 6- to 10-fold through inhibition of CYP3A4, OATP1B1, and P-gp, creating an extremely high risk of rhabdomyolysis.
Mecanismo
Simvastatin acid depends on CYP3A4 for metabolism, OATP1B1 for hepatocyte uptake, and P-gp for efflux; cyclosporine's broad transporter/enzyme inhibition blocks all clearance pathways.
Significância Clínica
This combination is contraindicated; multiple cases of severe and fatal rhabdomyolysis have been reported in transplant recipients.
Conduta
Contraindicated. Do not use simvastatin in patients taking cyclosporine. Use pravastatin or fluvastatin at low doses instead.