6β-Hydroxycortisol Is an Endogenous Probe for Evaluation of Drug-Drug Interactions Involving a Multispecific Renal Organic Anion Transporter, OAT3/SLC22A8, in Healthy Subjects

6 beta-Hydroxycortisol (6 beta-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 6 beta-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 6 beta-OHF (CLrenal, (6 beta-OHF)) compared with wild-type mice (18.1 +/- 1.5 versus 7.60 +/- 1.8 ml/min/kg). 6 beta-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. 6 beta-OHF plasma concentration and the amount of 6 beta-OHF excreted into the urine (X6 beta-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 6 beta-OHF (AUC(6 beta-OHF)) in studies 1 and 2, respectively, but did not affect X6 beta-OHF. Consequently, CLrenal, 6 beta-OHF (milliliters per minute) decreased significantly from 231 +/- 11 to 135 +/- 9 and from 225 +/- 26 to 141 +/- 12 after probenecid administration in studies 1 and 2, respectively. By contrast, neither AUC(6 beta-OHF) nor CLrenal, 6 beta-OHF was significantly altered by pyrimethamine administration. Taken together, these data suggest that OAT3 plays a significant role in the urinary excretion of 6 beta-OHF, and that 6 beta-OHF can be used to investigate the perpetrators of the pharmacokinetic drug interactions involving OAT3 in humans.