RT Journal Article
SR Electronic
T1 6<em>β</em>-Hydroxycortisol Is an Endogenous Probe for Evaluation of Drug–Drug Interactions Involving a Multispecific Renal Organic Anion Transporter, OAT3/<em>SLC22A8</em>, in Healthy Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 685
OP 694
DO 10.1124/dmd.113.055475
VO 42
IS 4
A1 Yuichiro Imamura
A1 Yuri Tsuruya
A1 Katja Damme
A1 Dominik Heer
A1 Yuji Kumagai
A1 Kazuya Maeda
A1 Nobuyuki Murayama
A1 Noriko Okudaira
A1 Atsushi Kurihara
A1 Takashi Izumi
A1 Yuichi Sugiyama
A1 Hiroyuki Kusuhara
YR 2014
UL http://dmd.aspetjournals.org/content/42/4/685.abstract
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 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.