Genetic variability in organic cation transporters: Pathophysiological manifestations and consequences for drug pharmacokinetics and efficacy

Naturally occurring genetic variants may affect expression and function of organic cation transporters. This may result in inter-individual variations of plasma and organ concentrations of endogenous molecules and drugs. Hence, genetic variants in the organic cation transporters may confer susceptibility to diseases and may cause variations in drug pharmacokinetics, efficacy and toxicity. This chapter gives a structured overview of the genetic variability in the human organic cation transporters and its consequences for disease susceptibility and therapeutic drug response. We present in a special depth the available information about genetically-determined loss of OCT1 activity and the consequences for the pharmacokinetics, efficacy and toxicity of drugs like metformin, morphine, tramadol and tropisetron. Another special focus is on polymorphisms in OCTN1 and OCTN2 as risk factors for Crohn’s disease. The third focus is on the accumulating data about the effects of regulatory polymorphisms in the MATE1 and MATE2K genes on metformin pharmacokinetics and efficacy. We also present meta-analyses of the currently available studies about the effects of the OCT2 polymorphism Ala270Ser on metformin pharmacokinetics.