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

• Published in: Drug metabolism and disposition Vol. 42; no. 4; pp. 685 - 694
• Main Authors: Imamura, Yuichiro, Tsuruya, Yuri, Damme, Katja, Heer, Dominik, Kumagai, Yuji, Maeda, Kazuya, Murayama, Nobuyuki, Okudaira, Noriko, Kurihara, Atsushi, Izumi, Takashi, Sugiyama, Yuichi, Kusuhara, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2014
• Subjects: Adult; Animals; Biomarkers - blood; Biomarkers - urine; Cell Culture Techniques; Drug Interactions; Female; Healthy Volunteers; HEK293 Cells; Humans; Hydrocortisone - analogs & derivatives; Hydrocortisone - blood; Hydrocortisone - urine; Kidney - drug effects; Kidney - metabolism; Male; Metabolic Clearance Rate; Mice; Mice, Knockout; Organic Anion Transporters, Sodium-Independent - genetics; Organic Anion Transporters, Sodium-Independent - metabolism; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Pharmaceutical Preparations - metabolism; Substrate Specificity; Young Adult; CLrenal sec; OCT; OAT; CLtot; AUCcortisol; MATE; X6β-OHF; DDI; 11β-HSD; hOAT; MPP; AUC; HEK; LC-MS/MS; 6β-OHF; CL6β-OHF; DX-619; AUC6β-OHF; CLrenal; PO
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.113.055475

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 amount of 6β-OHF excreted into the urine (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 studies 1 and 2, respectively, but did not affect X6β-OHF. Consequently, CLrenal, 6β-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 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.