Dataset Information

Determination of the endogenous OATP1B biomarkers glycochenodeoxycholate-3-sulfate and chenodeoxycholate-24-glucuronide in human and mouse plasma by a validated UHPLC-MS/MS method.

ABSTRACT: Glycochenodeoxycholate-3-sulfate (GCDCA-S) and chenodeoxycholate-24-glucuronide (CDCA-24G) are bile acid metabolites that potentially serve as endogenous biomarkers for drug-drug interactions mediated by the hepatic uptake transporters OATP1B1 and OATP1B3. We developed and validated a novel UHPLC-MS/MS method for the quantitative determination of GCDCA-S and CDCA-24G in mouse and human plasma with a lower limit of quantitation of 0.5 ng/mL. Chromatographic separation was achieved on an Accucore aQ column (50 mm × 2.1 mm, dp = 2.6 μm) maintained at 20 °C and a gradient mobile phase comprising 2 mM ammonium acetate in water and methanol. The extraction recoveries of GCDCA-S and CDCA-24G were >80 %, and linear (r² > 0.99) calibration curves ranged 0.5-100 ng/mL (CDCA-24G and GCDCA-S in mouse plasma) or 0.5-1000 ng/mL (GCDCA-S in mouse plasma). Values for precision (CV < 11.6 %) and accuracy bias (10.9 %) of analyte-spiked quality control samples verified that water was an acceptable matrix to prepare calibrators. This method was successfully applied to establish baseline activity of OATP1B1/OATP1B3 in humans and mice and establish the in vivo effects of OATP1B1/OATP1B3 inhibitors rifampin and micafungin.

SUBMITTER: Jin Y

PROVIDER: S-EPMC9588625 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Determination of the endogenous OATP1B biomarkers glycochenodeoxycholate-3-sulfate and chenodeoxycholate-24-glucuronide in human and mouse plasma by a validated UHPLC-MS/MS method.

Jin Yan Y Li Yang Y Eisenmann Eric D ED Figg William D WD Baker Sharyn D SD Sparreboom Alex A Hu Shuiying S

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 20220827

Glycochenodeoxycholate-3-sulfate (GCDCA-S) and chenodeoxycholate-24-glucuronide (CDCA-24G) are bile acid metabolites that potentially serve as endogenous biomarkers for drug-drug interactions mediated by the hepatic uptake transporters OATP1B1 and OATP1B3. We developed and validated a novel UHPLC-MS/MS method for the quantitative determination of GCDCA-S and CDCA-24G in mouse and human plasma with a lower limit of quantitation of 0.5 ng/mL. Chromatographic separation was achieved on an Accucore ...[more]

PMID: 36054985

Similar Datasets

Project description:The liver is an important organ for drugs disposition, and thus how to accurately evaluate hepatic clearance is essential for proper drug dosing. However, there are many limitations in drug dosage adjustment based on liver function and pharmacogenomic testing. In this study, we evaluated the ability of endogenous glycochenodeoxycholate-3-sulfate (GCDCA-S) and 4β-hydroxycholesterol (4β-HC) plasma levels to evaluate organic anion-transporting polypeptide (Oatps)-mediated hepatic uptake and Cyp3a-meidated metabolism of atorvastatin (ATV) in rats. The concentration of ATV and its metabolites, 2-OH ATV and 4-OH ATV, was markedly increased after a single injection of rifampicin (RIF), an inhibitor of Oatps. Concurrently, plasma GCDCA-S levels were also elevated. After a single injection of the Cyp3a inhibitor ketoconazole (KTZ), plasma ATV concentrations were significantly increased and 2-OH ATV concentrations were decreased, consistent with the metabolism of ATV by Cyp3a. However, plasma 4β-HC was not affected by KTZ treatment despite it being a Cyp3a metabolite of cholesterol. After repeated oral administration of RIF, plasma concentrations of ATV, 2-OH ATV and 4-OH ATV were markedly increased and the hepatic uptake ratio of ATV and GCDCA-S was decreased. KTZ did not affect plasma concentrations of ATV, 2-OH ATV and 4-OH ATV, but significantly decreased the metabolic ratio of total and 4-OH ATV. However, the plasma level and hepatic metabolism of 4β-HC were not changed by KTZ. The inhibition of hepatic uptake of GCDCA-S by RIF was fully reversed after a 7-d washout of RIF. Plasma concentration and hepatic uptake ratio of GCDCA-S were correlated with the plasma level and hepatic uptake of ATV in rats with ANIT-induced liver injury, respectively. These results demonstrate that plasma GCDCA-S is a sensitive probe for the assessment of Oatps-mediated hepatic uptake of ATV. However, Cyp3a-mediated metabolism of ATV was not predicted by plasma 4β-HC levels in rats.

Dataset Information

Determination of the endogenous OATP1B biomarkers glycochenodeoxycholate-3-sulfate and chenodeoxycholate-24-glucuronide in human and mouse plasma by a validated UHPLC-MS/MS method.

Publications

Determination of the endogenous OATP1B biomarkers glycochenodeoxycholate-3-sulfate and chenodeoxycholate-24-glucuronide in human and mouse plasma by a validated UHPLC-MS/MS method.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets