Differential inhibition features of direct-acting anti-hepatitis C virus agents against human organic anion transporting polypeptide 2B1

Simeprevir (SMV), asunaprevir (ASV), daclatasvir (DCV) and sofosbuvir (SOF), which are direct-acting Antiviral (DAA) agents, are expected to become essential pharmaceutical tools in the fight against the hepatitis C virus (HCV). However, because DAAs are taken orally, there is a potential risk of drug-drug interactions (DDIs) at the absorption step with co-administered drugs in the small intestine. Since it is known that organic anion transporting polypeptide 2B1 (OATP2B1) is one of the key transporters contributing to intestinal drug absorption, it is important to thoroughly understand the inhibition profiles of various DAAs in relation to OATP2B1 function in order to avoid unexpected DDIs. Therefore, using a cell-based transport assay, this study aimed at clarifying such DAA inhibition characteristics towards OATP2B1 function. The results of co-incubation inhibition assays showed that SMV and ASV strongly inhibited estrone sulfate (5 nM) uptake by OATP2B1, with half maximal inhibitory concentrations of 0.49 ± 0.12 μM and 0.16 ± 0.06 μM, respectively. Furthermore, it was found that SMV and ASV imposed long-lasting pre-incubation inhibitory effects on OATP2B1 function that enhanced their co-incubation inhibition potencies. On the other hand, no (or much less significant) inhibitory effects were observed for SOF or DCV. To summarise, these results show that SMV and ASV are co-incubation, as well as long-lasting pre-incubation, inhibitors of OATP2B1 function and therefore these inhibitions may lead to clinically relevant DDIs when used with OATP2B1 substrates.