Effect of cyclosporine A and tacrolimus on OATP1B1 mediated transport of atorvastatin in an in vitro whole cell model

Abstract

BACKGROUND: Dyslipidaemia is more frequent in solid organ transplant recipients than in the general population. In order to reduce the overall cardiovascular risk in transplant patients lipid-lowering drugs, especially statins, have become widely used. However, the use of statins in transplant recipients taking cyclosporine A (CsA) results in significantly increased risk for statin induced side-effects such as myopathy and also rhabdomyolysis. Statin plasma concentrations are also increased several-fold and may be responsible for this increased risk. The other calcineurin inhibitor, tacrolimus (Tac), does not present such an effect on statin plasma concentrations during ordinary clinical use. AIM AND METHOD: The present study elucidated the in vitro cellular aspects and the mechanism of the pharmacokinetic interaction between atorvastatin (HMg-CoA reductase inhibitor) and the two calcineurin inhibitors, CsA and Tac. The inhibitory effect of CsA and Tac on cellular uptake of atorvastatin via the organic anion transporter polypeptide 1B1 (OATP1B1) was investigated in an in vitro over expression whole cell model. RESULTS: Atorvastatin was shown to be transported via the OATP1B1 transporter since cellular uptake was higher in OATP1B1 transfected HEK293 cells compared to mock cells. Inhibition of cellular uptake of atorvastatin was observed with CsA in OATP1B1 transfected cells. No clear inhibition of cellular uptake of atorvastatin was however observed for Tac in the OATP1B1 model, at least not in the lower concentration range investigated. CONCLUSION: The present in vitro study indicates that the cellular uptake of atorvastatin is mediated by OATP1B1 transporters and that CsA inhibits this drug transport. Tac on the other hand did not interfere with cellular uptake of atorvastatin, at least not in the concentration range investigated in this thesis. The observed interaction between atorvastatin and CsA is in line with findings in previous clinical studies, however further investigations is necessary in order to further characterize these findings.