RT Journal Article SR Electronic T1 Functional consequences of pravastatin isomerization on OATP1B1 mediated transport JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP DMD-AR-2020-000122 DO 10.1124/dmd.120.000122 A1 Jonathan B. Wagner A1 Melissa Ruggiero A1 J. Steven Leeder A1 Bruno Hagenbuch YR 2020 UL http://dmd.aspetjournals.org/content/early/2020/09/05/dmd.120.000122.abstract AB Pravastatin (PVA) can be isomerized to its inactive metabolite 3'α-iso-pravastatin acid (3αPVA) under acidic pH conditions. Previous studies reported inter-individual differences in circulating concentrations of PVA and 3αPVA. This study investigated the functional consequences of PVA isomerization on OATP1B1-mediated transport. We characterized 3αPVA inhibition of OATP1B1-mediated PVA uptake into HEK293 cells expressing the four different OATP1B1 proteins (*1a, *1b, *5 and *15). 3αPVA inhibited OATP1B1-mediated PVA uptake in all four OATP1B1 gene products but with lower IC50/Ki values for OATP1B1*5 and *15 than for the reference proteins (*1a and *1b). PVA and 3αPVA were transported by all four OATP1B1 proteins. Kinetic experiments revealed that maximal transport rates (Vmax values) for OATP1B1 variants *5 and *15 were lower than for *1a and *1b for both substrates. Apparent affinities for 3αPVA transport were similar for all four variants. However, the apparent affinity of OATP1B1*5 for 3αPVA was higher (lower Km value) than for PVA. These data confirm that PVA conversion to 3αPVA can have functional consequences on PVA uptake and impacts OATP1B1 variants more than the reference protein, thus highlighting another source variation that must be taken into consideration when optimizing the PVA dose-exposure relationship for patients. Significance Statement 3’α-iso-pravastatin acid inhibits pravastatin uptake for all OATP1B1 protein types, however, the IC50 values were significantly lower in OATP1B1*5 and *15 transfected cells. This suggests that a lower concentration of 3’α-iso-pravastatin is needed to disrupt OATP1B1-mediated pravastatin uptake, secondary to decreased cell surface expression of functional OATP1B1 in variant expressing cells. These data will refine previous pharmacokinetic models that are utilized to characterize pravastatin inter-individual variability with an ultimate goal of maximizing efficacy at the lowest possible risk for toxicity.