Organic cation transporters (OCTs) of the solute carrier family (SLC) 22 and multidrug and toxin extrusion (MATE) transporters of the SLC47 family have been identified as uptake and efflux transporters, respectively, for xenobiotics including several clinically used drugs such as the antidiabetic agent metformin, the antiviral agent lamivudine, and the anticancer drug oxaliplatin. Expression of human OCT1 (SLC22A1) and OCT2 (SLC22A2) is highly restricted to the liver and kidney, respectively. By contrast, OCT3 (SLC22A3) is more widely distributed. MATEs (SLC47A1, SLC47A2) are predominantly expressed in human kidney. Data on in vitro studies reporting a large number of substrates and inhibitors of OCTs and MATEs are systematically summarized. Several genetic variants of human OCTs and in part of MATE1 have been reported, and some of them result in reduced in vitro transport activity corroborating data from studies with knockout mice. A comprehensive overview is given on currently known genotype-phenotype correlations for variants in OCTs and MATE1 related to protein expression, pharmacokinetics/-dynamics of transporter substrates, treatment outcome, and disease susceptibility.

6b-Hydroxycortisol (6b-OHF) is a substrate of the organic anion transporter 3 (OAT3) and the multidrug and toxin extrusion proteins MATE1 and MATE-2K in the corresponding cDNA-transfected cells. This study aimed to examine the contribution of OAT3 and MATEs to the urinary excretion of 6b-OHF in humans using the appropriate in vivo inhibitors, probenecid and pyrimethamine, for OAT3 and MATEs, respectively. Oat3(-/-) mice showed significantly reduced renal clearance of 6b-OHF (CL renal, 6b-OHF ) compared with wild-type mice (18.1 6 1.5 versus 7.60 6 1.8 ml/min/kg). 6b-OHF uptake by human kidney slices was inhibited significantly by probenecid to 20-45% of the control values and partly by 1-methyl-4-phenylpyridinium. 6b-OHF plasma concentration and the amount of 6b-OHF excreted into the urine (X 6b-OHF ) were measured in healthy subjects enrolled in drug-drug interaction studies of benzylpenicillin alone or with probenecid (study 1), adefovir alone or with probenecid (study 2), and metformin alone or with pyrimethamine (study 3). Probenecid treatment caused a 57 and 76% increase in the area under the plasma concentration-time curve for 6b-OHF (AUC 6b-OHF ) in studies 1 and 2, respectively, but did not affect X 6b-OHF . Consequently, CL renal, 6b-OHF (milliliters per minute) decreased significantly from 231 6 11 to 135 6 9 and from 225 6 26 to 141 6 12 after probenecid administration in studies 1 and 2, respectively. By contrast, neither AUC 6b-OHF nor CL renal, 6b-OHF was significantly altered by pyrimethamine administration. Taken together, these data suggest that OAT3 plays a significant role in the urinary excretion of 6b-OHF, and that 6b-OHF can be used to investigate the perpetrators of the pharmacokinetic drug interactions involving OAT3 in humans.