14.7: Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters

The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms within these transporter genes can significantly alter drug bioavailability and therapeutic outcomes, making them essential targets in the pursuit of personalized medicine.

P-glycoprotein (P-gp), encoded by the ABCB1 gene, is one of the most extensively studied efflux transporters. It expels a wide range of drugs—including anticancer agents like vincristine, cardiac drugs like digoxin, and immunosuppressants like tacrolimus—thereby limiting their intracellular accumulation. Several single-nucleotide polymorphisms (SNPs) in ABCB1, notably 3435C>T, 2677T>G, and 1236C>T, have been shown to influence P-gp expression and function. For instance, certain ABCB1 haplotypes involving the 3435T allele have been associated with altered P-gp expression and drug bioavailability, although clinical findings remain inconsistent. However, clinical findings remain variable due to the complexity of haplotype structures and gene-gene interactions. These polymorphisms also impact drug distribution into pharmacologic sanctuary sites such as the brain and testes, contributing to drug resistance and altered treatment responses in certain diseases.

In contrast, solute carrier transporters such as OATP1B1, encoded by SLCO1B1, facilitate drug influx, particularly into hepatic tissue. Over 40 non-synonymous SNPs have been identified in SLCO1B1, with the c.521T>C variant being among the most clinically relevant. This polymorphism reduces transporter activity, resulting in higher plasma concentrations of drugs like simvastatin and an elevated risk of dose-dependent myopathy. Allelic variants, including SLCO1B1 *5, *15, and *17, are found at frequencies ranging from 5% to 20% in many populations, highlighting the need for genotype-guided dosing in patients receiving statins. A clearer understanding of transporter genetics enhances the ability to tailor pharmacotherapy, reduce adverse effects, and improve clinical outcomes through the use of individualized treatment strategies.