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Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs
Author(s) -
Mori Daiki,
Kimoto Emi,
Rago Brian,
Kondo Yusuke,
KingAhmad Amanda,
Ramanathan Ragu,
Wood Linda S.,
Johnson Jillian G.,
Le Vu H.,
Vourvahis Manoli,
David Rodrigues A.,
Muto Chieko,
Furihata Kenichi,
Sugiyama Yuichi,
Kusuhara Hiroyuki
Publication year - 2020
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1695
Subject(s) - rifampicin , atorvastatin , pharmacology , rosuvastatin , drug , biomarker , medicine , therapeutic drug monitoring , chemistry , antibiotics , biochemistry
To address the most appropriate endogenous biomarker for drug–drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate‐3‐glucuronide, glycochenodeoxycholate‐3‐sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose‐dependent change in area under the plasma concentration‐time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC 0‐24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR −1 vs. rifampicin plasma C max (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B‐mediated drug–drug interaction risk assessment approaches based on agency guidelines in early clinical trials.