Association Study of OATP1B3 Polymorphisms on Hepatic Uptake and Drug–Drug Interaction <i>In Vitro</i>

The OATP1B3 transporter is responsible for the hepatic uptake of multiple drugs and their metabolites. The single-nucleotide polymorphism (SNP) of OATP1B3 may be essential for interindividual variability in drug response. The distribution of nonsynonymous SNPs was defined within the Chinese Han population. The SNPs rs4149117 and rs7311358, corresponding to Ser112Ala and Met233Ile substitutions, were confirmed as the most frequent alleles. The effect of coding variants on the OATP1B3-based activity was assessed on HEK293A cells with stable gene expression. The uptake and inhibitory profiles of compounds were compared between variants and the wild-type (WT). Despite the altered transport velocity, the Michaelis-Menten constant for Ser112Ala, Met233Ile, and SM/AI (combined mutations) was comparable to that for the WT. Likewise, the inhibition of ³H-estradiol-17-β-d-glucuronide (³H-EG) uptake by OATP1B3 ranked in the order of potency was WT > variants, which suggested the drug-drug interaction rarely occurred. Moreover, molecular docking studies of estrone sulfate (ES) and EG with OATP1B3 and its clinically relevant variants identified critical residues for substrate binding. The SNPs rs4149117 and rs7311358 did not alter key interactions. The difference in the docking score was less than 0.15 kcal/mol. Consequently, the variants were unlikely to affect the pharmacokinetics of the OATP1B3 substrates. It was interpreted that the variants did not contribute to clinically relevant changes. However, because effects are substrate-specific and other hepatic transporters may compensate, final clinical interpretation should be substrate- and evidence-based. Targeted pharmacokinetics and pharmacogenetic studies remain necessary for drugs where OATP1B3 is a major disposition determinant.