Abstract
Differences in the expression and function of the organic anion transporting polypeptide (OATP) transporters contribute to inter-individual variability in atorvastatin clearance. However, the importance of the bile acid transporter NTCP (SLC10A1) in atorvastatin uptake clearance (CLupt) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CLupt in twelve human liver samples. The impact of inhibition on atorvastatin CLupt was also studied, using inhibitors of different isoform specificities. Expression levels of the four transport proteins were quantified by LC-MS/MS. These data, together with atorvastatin in vitro kinetics, were used to predict the maximal transport activity (MTA) and inter-individual differences in CLupt of each transporter in vivo. Subsequently, hepatic uptake impairment upon co-administration of five clinically interacting drugs was predicted using in vitro inhibitory potencies. NTCP and OATP protein expression varied 3.7- to 32-fold among the twelve sample donors. The rank order in expression was OATP1B1 > OATP1B3 ≈ NTCP ≈ OATP2B1. NTCP was found to be of minor importance in atorvastatin disposition. Instead, OATP1B1 and OATP1B3 were confirmed as the major atorvastatin uptake transporters. The average contribution to atorvastatin uptake was OATP1B1 > OATP1B3 >> OATP2B1 > NTCP, although this rank order varied between individuals. The inter-individual differences in transporter expression and CLupt resulted in marked differences in drug-drug interactions due to isoform-specific inhibition. We conclude that this variation should be considered in in vitro to in vivo extrapolations.
- active transport
- drug clearance
- drug-drug interactions
- hepatic transport
- hepatic uptake
- hepatocytes
- in vitro-in vivo prediction
- in vitro-in vivo scaling
- organic anion transport
- proteomics
- The American Society for Pharmacology and Experimental Therapeutics