The SLC organic anion-transporter family member 1B1 (SLCO1B1) gene, for example, encodes an organic anion transporter 1B1 (OATP1B1) that is located primarily on the sinusoidal face of human hepatocytes. OATP1B1 mediates the hepatic uptake of many endogenous compounds (e.g., bilirubin) and xenobiotics such as 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (e.g., simvastatin) from sinusoidal blood, resulting in their net excretion from blood, likely via biliary excretion. A common sequence variant in the coding region of SLCO1B1 (rs4149056) decreases the trans port activity of the encoded protein and results in markedly increased plasma concentrations of drugs that are eliminated from the blood via hepatic uptake. Using GWAS, correlations have been established between variants in SLCO1B1 and myopathy after treatment with the HMG-CoA reductase inhibitor simvastin.[1]

In the field of hematology, a GWAS identified the rs4149056 and other variants in SLCO1B1 to be significantly associated with MTX clearance; this association was robustly confirmed with five different MTX treatment regimens in more than 1000 pediatric ALL patients. [2] MTX is mainly excreted in the kidney, and SLCO1B1 is expressed in the liver and associated with hepatobiliary excretion, which is a relatively minor path for MTX elimination (less than 30%). However, results of targeted urinary metabolome analyses suggest that dysfunction of OATP1B1 in the liver may affect the excretion profile of endogenous and exogenous substrates through metabolite-mediated interactions, thereby influencing other transport systems in distant organs (e.g., MTX excretion in the kidney). [3] Clearly, further investigations are necessary to better characterize such a comprehensive concept of complex interactions between transporters and their substrates.

References

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[1] Roden DM, McLeod HL, Relling MV, et al. Pharmacogenomics. Lancet. 2019;394(10197):521–532.

[2] Ramsey LB, Panetta JC, Smith C, et al. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood. 2013;121(6):898–904.

[3] Martinez D, Muhrez K, Woillard JB, et al. Endogenous metabolites mediated communication between OAT1/OAT3 and OATP1B1 may explain the association between SLCO1B1 SNPs and methotrexate toxicity. Clin Pharmacol Ther. 2018;104(4):687–698.

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