Hepatic drug transporters in pharmacotherapy: mechanisms, therapeutic targeting, and clinical translation.

Hepatic membrane transporters are key determinants of drug disposition, hepatocellular exposure, pharmacodynamic response, drug-drug interactions (DDIs), and hepatobiliary toxicity. Among these, the organic anion transporting polypeptides OATP1B1 and OATP1B3, sodium taurocholate cotransporting polypeptide (NTCP), and bile salt export pump (BSEP) coordinate hepatic uptake and biliary efflux of endogenous compounds, therapeutic agents, and metabolites. Their role in transporter-mediated pharmacokinetics, exposure-response relationships, therapeutic efficacy, DDIs, and drug-induced liver injury (DILI) is critically reviewed. Specific focus is placed on transporter inhibition, competition, saturation, and disease-associated regulation that can lead to clinically relevant changes in hepatic and systemic drug exposure. Pharmacogenomic variation, including variation in SLCO1B1, SLCO1B3, SLC10A1, and ABCB11, is considered together with inflammation and chronic liver disease as determinants of transporter phenotype and interindividual variability. BSEP is described in more detail as a key hepatobiliary safety determinant including impaired bile-acid export, cholestatic liability, and implications for DILI assessment and drug development. Clinical evidence is differentiated from pre-clinical transporter-targeting concepts. NTCP-directed antiviral therapy is an important example of clinical pharmacological translation, while many transporter-guided delivery systems are still experimental. Therefore, selected prodrug, ligand-directed, and nanocarrier strategies are only discussed where transporter engagement is associated with pharmacokinetic, pharmacodynamic, efficacy, safety, or translational consequences. Finally, transporter-informed PBPK modeling, human-relevant models, and biomarker-guided stratification are discussed to improve DDI prediction, risk assessment, and precision dosing. This pharmacology-focused framework defines when transporter modulation or targeting may be therapeutically beneficial and when it may introduce pharmacokinetic or safety liabilities.