6β-Hydroxycortisol is an endogenous probe for evaluation of drug-drug interactions involving a multispecific renal organic anion transporter, OAT3/SLC22A8, in healthy subjects.
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 (CL(renal, 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 (X(6β-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 (AUC(6β-OHF)) in studies 1 and 2, respectively, but did not affect X(6β-OHF). Consequently, CL(renal, 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 AUC(6β-OHF) nor CL(renal, 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.
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (Y.I., N.M., N.O., A.K., T.I.); Daiichi Sankyo Tissue and Cell Research Center Munich, Daiichi Sankyo Europe GmbH, Martinsried, Germany (K.D., D.H.); Clinical Trial Center, Kitasato East Hospital, Sagamihara, Kanagawa, Japan (Y.K.); Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Kanagawa, Japan (Y.S.); and Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.T., K.M., H.K.).
Yuichiro
Y
Imamura
Yuri
Y
Tsuruya
Katja
K
Damme
Dominik
D
Heer
Yuji
Y
Kumagai
Kazuya
K
Maeda
Nobuyuki
N
Murayama
Noriko
N
Okudaira
Atsushi
A
Kurihara
Takashi
T
Izumi
Yuichi
Y
Sugiyama
Hiroyuki
H
Kusuhara
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D018929:Cell Culture Techniques; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013379:Substrate Specificity; D055815:Young Adult
D015415:Biomarkers; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D004364:Pharmaceutical Preparations; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; C114338:organic anion transport protein 3; C001380:6 beta-hydroxycortisol; D006854:Hydrocortisone