PT - JOURNAL ARTICLE AU - Imamura, Yuichiro AU - Tsuruya, Yuri AU - Damme, Katja AU - Heer, Dominik AU - Kumagai, Yuji AU - Maeda, Kazuya AU - Murayama, Nobuyuki AU - Okudaira, Noriko AU - Kurihara, Atsushi AU - Izumi, Takashi AU - Sugiyama, Yuichi AU - Kusuhara, Hiroyuki TI - 6β-hydroxycortisol is an Endogenous Probe for Evaluation of Drug-drug Interaction Involving a Multispecific Renal Organic Anion Transporter, OAT3/<em>SLC22A8</em>, in Healthy Subjects AID - 10.1124/dmd.113.055475 DP - 2014 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.113.055475 4099 - http://dmd.aspetjournals.org/content/early/2014/01/31/dmd.113.055475.short 4100 - http://dmd.aspetjournals.org/content/early/2014/01/31/dmd.113.055475.full AB - 6β-hydroxycortisol (6β-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 6β-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 6β-OHF (CLrenal, 6β-OHF) compared with wild-type mice (18.1±1.5 versus 7.60±1.8 ml/min/kg). 6β-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. 6β-OHF plasma concentration and the urinary excretion of 6β-OHF (X6β-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 6β-OHF (AUC6β-OHF) in Study 1 and 2, respectively, but did not affect X6β-OHF. Consequently, CLrenal, 6β-OHF (ml/min) decreased significantly from 231±11 to 135±9 and from 225±26 to 141±12 after probenecid administration in Study 1 and 2, respectively. By contrast, neither AUC6β-OHF nor CLrenal, 6β-OHF was significantly altered by pyrimethamine administration. Taken together, these data suggest that OAT3 plays a significant role in the urinary excretion of 6β-OHF, and that 6β-OHF can be used to investigate the perpetrators of the pharmacokinetic drug interactions involving OAT3 in humans.