Identification of nonsynonomous polymorphisms of human organic anion transporting polypeptide-A (OATP-A) associated with altered transport activity

Organic anion transporting polypeptides (OATP) are a growing family of uptake transporters important to drug disposition. Studies from this laboratory have shown that OATP-A (SLC21A3) is selectively expressed in human intestine as well as kidney and brain. Accordingly, variability in the expression or function of this polyspecific drug uptake transporter may have important implications to bioavailability and tissue penetration of substrate drugs. In order to determine the extent of genetic heterogeneity in OATP-A, PCR-based genotyping analyses were carried out on ethnically defined genomic DNA samples (n=96 each for African-, Chinese-, European-, and Hispanic-Americans). We identified three novel nonsynonymous polymorphisms within the coding region of OATP-A; T38C (Ile38Thr), A516C (Glu172Asp) and G559A (Ala187Thr). Genotypic frequencies of these polymorphisms were dependent on race. In vitro functional assessment revealed that the A516C (Glu172Asp) variant had markedly reduced capacity for mediating the cellular uptake of OATP-A substrates, estrone sulfate and fexofenadine. Cell surface biotinylation experiments did not show altered plasma membrane expression of the transporter, suggesting the reduced transport activity associated with the A516C variant is likely due to altered intrinsic activity of the transporter. Our data suggest that OATP-A polymorphisms may contribute to inter-individual variability in intestinal absorption and CNS penetration of substrate drugs. Clinical Pharmacology & Therapeutics (2004) 75, P93–P93; doi: 10.1016/j.clpt.2003.11.355