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

Abstract

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

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

“…Recently, many researchers have focused on the mechanism of drug-induced hyperbilirubinemia (Zucker et al, 2001;Campbell et al, 2004;Chang et al, 2013;Wlcek et al, 2013;Chiou et al, 2014); however, the exact mechanism of drug-induced hyperbilirubinemia in humans and the relationship between the biomarkers and DDI from a quantitative perspective have not been elucidated. In other cases, previous studies have shown that when the renal transporters were inhibited by drugs, the plasma concentrations of creatinine, N-methylnicotinamide, and 6b-hydroxycortisol increased with the inhibition of OCT2 and/or MATEs, MATEs, and OAT3 by drugs, respectively (Imamura et al, 2011(Imamura et al, , 2014Ito et al, 2012). The utility of an endogenous substrate as a biomarker for transporter inhibition has been a topic of great interest.…”

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

“…Other metrics of cortisol and its metabolites have been explored, such as the formation clearance of 6b-hydroxycortisol and a summed formation clearance of 6b-hydroxycortisol and 6b-hydroxycortisone (Luo et al, 2009;Peng et al, 2011). Because 6b-hydroxycortisol was found to be a substrate of the renal organic anion transporter 3, urinary 6b-hydroxycortisol/cortisol metabolic ratios may be affected if organic anion transporter 3 function is altered (Imamura et al, 2014).…”

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

“…Therefore, the availability of endogenous biomarkers to assess transporter activities during early drug development would have substantial benefits for the pharmaceutical industry in order to avoid expensive clinical trials and also minimize the risk of late-stage failures and even drug withdrawal. In this regard, many attempts have been made to identify endogenous compounds that could reflect the activities of enzymes and transporters, such as CYP3A4 (Kanebratt et al, 2008;Diczfalusy et al, 2011;Shin et al, 2013;Kasichayanula et al, 2014), CYP2D6 (Tay-Sontheimer et al, 2014), MATEs (Ito et al, 2012;Kato et al, 2014;Müller et al, 2015), and OAT3 (Imamura et al, 2014) to improve prediction of DDI. However, as far as we know, no validated in vivo clinical endogenous probe of OATP1B has been identified.…”