Proposal of a Parameter for OATP1B1 Inhibition Screening at the early Drug Discovery Stage

Abstract It is known that potent inhibition of organic anion transporting polypeptide (OATP)1B1 increases exposure to statins, leading to severe adverse effects. The aim of this study is to propose a parameter and its criteria in OATP1B1 inhibition assay at the early drug discovery stage in order to avoid compounds with the risk of statin-related adverse effects. According to drug label information, most of compounds classified as “contraindicated” or “should be avoided” when administered concomitantly with statins increased their AUCs more than 4-fold. Generally, R values where R=1+plasma unbound fraction (fu)×maximum inhibitor concentration at the inlet to the liver/IC50 are used to evaluate the extent of clinical drug interaction. However, clinical doses and Cmax cannot be determined at the screening stage. Therefore, we estimated the correlations between change in AUC of statins concomitantly administered with OATP1B1 inhibitors and various parameters including fu/IC50. Cyclosporin A, rifampicin, and telaprevir increased the AUC of statins more than 4-fold and fu/IC50 of these compounds were > 0.1 L/μmol. On the other hand, fu/IC50 of other compounds were ≤ 0.03 L/μmol. This study indicates that fu/IC50 is a useful parameter to avoid compounds that seriously affect statin potency through interaction with OATP1B1 at the screening stage.