Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1)

Abstract

OATP1B1 (SLCO1B1) is predominantly expressed at the basolateral membrane of hepatocytes and is critically important for the hepatic uptake and clearance of numerous drug substrates and endogenous compounds. In general, the organic anion transporting polypeptides (OATP; SLCO) represent a superfamily of uptake transporters that mediate the sodium-independent transport of a diverse range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic peptides, numerous drugs and other xenobiotic substances. OATP1B1 is highly polymorphic and a number of relevant and ethnically dependent polymorphisms have been identified and functionally characterized. In particular, the SLCO1B1 521T>C and 388A>G polymorphisms are commonly occurring variants in ethnically diverse populations and numerous in vitro and clinical studies have evaluated the consequences of these variants to interindividual differences in drug disposition and response. OATP1B1 is particularly important for the disposition of HMG-CoA reductase inhibitors, or statins, as it is known to efficiently transport most statins to their site of action within hepatocytes. Many studies have focused on the consequences of OATP1B1 variants to statin disposition in vitro and in vivo and would suggest that genetic variability in SLCO1B1 has important implications for statin pharmacokinetics, risk for statin-induced myopathy, and modulation of statin treatment response. This review describes what is currently known regarding SLCO1B1 genotype, OATP1B1 protein expression and interindividual and interethnic consequences to drug disposition, with particular focus on statin pharmacokinetics and implications for drug response and toxicity.

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

“…Human OATP1B plays pivotal roles in the hepatic uptake of a diverse array of anionic drugs. [7][8][9] As expected, potent OATP1B inhibitors, such as cyclosporine A and rifampicin, have been shown to increase (2-fold to 16-fold) the area under the plasma concentration-time curve (AUC) of OATP1B substrate drugs (UW Drug Interaction Database Program, https ://www.drugi ntera ction info.org/). We and other groups have demonstrated significant increases in the plasma concentrations of endogenous substrates such as bilirubins, coproporphyrins, amidated and nonamidated bile acids (including glucuronide and sulfate conjugates), and dicarboxylates following a single dose of cyclosporine A, rifampicin, and selected NCEs with OATP1B inhibition potential.…”

“…Human OATP1B plays pivotal roles in the hepatic uptake of a diverse array of anionic drugs . As expected, potent OATP1B inhibitors, such as cyclosporine A and rifampicin, have been shown to increase (2‐fold to 16‐fold) the area under the plasma concentration‐time curve (AUC) of OATP1B substrate drugs (UW Drug Interaction Database Program, https://www.druginteractioninfo.org/).…”

Comparative Effectiveness of Combination Therapy with Statins and Angiotensin‐Converting Enzyme Inhibitors versus Angiotensin II Receptor Blockers in Patients with Coronary Heart Disease: A Nationwide Population‐Based Cohort Study in Korea

“…First, the NHIS database contains information on a population that is ethnically homogeneous. Studies suggested an interethnic variability in pharmacologic responses to medications . For example, Asian individuals are more responsive to the beneficial effects of statins .…”

“…Studies suggested an interethnic variability in pharmacologic responses to medications. [39][40][41][42][43] For example, Asian individuals are more responsive to the beneficial effects of statins. 39 Also, differences in responses to antihypertensive medications exist between whites and African Americans.…”

Role of Genetic Variations in the Hepatic Handling of Drugs

“…To date, almost 200 SNPs in the SLCO1B1 gene have been described, some of them very frequent, such as c.388A>G (p.Asn130Asp, rs2306283), whose minor allele frequency (MAF) is 42.8%. This variant has less capacity to transport certain drugs, for instance, repaglinide [9,10]. However, this does not result in an important impact on the pharmacokinetics, response and toxicity of these drugs.…”