Identification of Glycochenodeoxycholate 3-O-Glucuronide and Glycodeoxycholate 3-O-Glucuronide as Highly Sensitive and Specific OATP1B1 Biomarkers.

Autor: Neuvonen M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland., Hirvensalo P; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland., Tornio A; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland., Rago B; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., West M; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Lazzaro S; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Mathialagan S; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Varma M; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Cerny MA; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Costales C; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Ramanathan R; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Rodrigues AD; ADME Sciences, Medicine Design, Pfizer Inc., Groton, Connecticut, USA., Niemi M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2021 Mar; Vol. 109 (3), pp. 646-657. Date of Electronic Publication: 2020 Oct 18.
DOI: 10.1002/cpt.2053
Abstrakt: The aim of this study was to investigate the sensitivity and specificity of endogenous glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) as substrates for organic anion transporting polypeptide 1B1 (OATP1B1) in humans. We measured fasting levels of plasma GCDCA-3G and GDCA-3G using liquid chromatography-tandem mass spectrometry in 356 healthy volunteers. The mean plasma levels of both compounds were ~ 50% lower in women than in men (P = 2.25 × 10 -18 and P = 4.73 × 10 -9 ). In a microarray-based genome-wide association study, the SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) variation showed the strongest association with the plasma GCDCA-3G (P = 3.09 × 10 -30 ) and GDCA-3G (P = 1.60 × 10 -17 ) concentrations. The mean plasma concentration of GCDCA-3G was 9.2-fold (P = 8.77 × 10 -31 ) and that of GDCA-3G was 6.4-fold (P = 2.45x10 -13 ) higher in individuals with the SLCO1B1 c.521C/C genotype than in those with the c.521T/T genotype. No other variants showed independent genome-wide significant associations with GCDCA-3G or GDCA-3G. GCDCA-3G was highly efficacious in detecting the SLCO1B1 c.521C/C genotype with an area under the receiver operating characteristic curve of 0.996 (P < 0.0001). The sensitivity (98-99%) and specificity (100%) peaked at a cutoff value of 180 ng/mL for men and 90 ng/mL for women. In a haplotype-based analysis, SLCO1B1*5 and *15 were associated with reduced, and SLCO1B1*1B, *14, and *35 with increased OATP1B1 function. In vitro, both GCDCA-3G and GDCA-3G showed at least 6 times higher uptake by OATP1B1 than OATP1B3 or OATP2B1. These data indicate that the hepatic uptake of GCDCA-3G and GDCA-3G is predominantly mediated by OATP1B1. GCDCA-3G, in particular, is a highly sensitive and specific OATP1B1 biomarker in humans.
(© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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