title: Leveraging of Rifampicin-Dosed Cynomolgus Monkeys to Identify Bile Acid 3-O-Sulfate Conjugates as Potential Novel Biomarkers for Organic Anion-Transporting Polypeptides.
abstract: In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10, and 30 mg/kg) that generated plasma-freeCmaxvalues (0.06, 0.66, 2.57, and 7.79µM, respectively) spanning the reported in vitro IC50values for OATP1B1 and OATP1B3 (≤1.7μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v.2H4-pitavastatin, 0.2 mg/kg) was increased 1.2-, 2.4-, 3.8-, and 4.5-fold, respectively. Plasma of RIF-dosed cynomolgus monkeys was subjected to a liquid chromatography-tandem mass spectrometry method that supported the analysis of 30 different BAs. Monkey urine was profiled, and we also determined that the impact of RIF on BA renal clearance was minimal. Although sulfated BAs comprised only 1% of the plasma BA pool, a robust RIF dose response (maximal ≥50-fold increase in plasma AUC) was observed for the sulfates of five BAs [glycodeoxycholate (GDCA-S), glycochenodeoxycholate (GCDCA-S), taurochenodeoxycholate, deoxycholate (DCA-S), and taurodeoxycholate (TDCA-S)]. In vitro, RIF (≤100μM) did not inhibit cynomolgus monkey liver cytosol-catalyzed BA sulfation and cynomolgus monkey hepatocyte-mediated uptake of representative sulfated BAs (GDCA-S, GCDCA-S, DCA-S, and TDCA-S) was sodium-independent and inhibited (≥70%) by RIF (5μM); uptake of taurocholic acid was sensitive to sodium removal (74% decrease) and relatively refractory to RIF (≤21% inhibition). We concluded that sulfated BAs may serve as sensitive biomarkers of cynomolgus monkey OATPs and that exploration of their utility as circulating human OATP biomarkers is warranted.
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Rhishikesh
authors.initials: R
authors.lastname: Thakare
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Hongying
authors.initials: H
authors.lastname: Gao
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kosa
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Bi
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Manthena V S
authors.initials: MVS
authors.lastname: Varma
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cerny
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Max
authors.initials: M
authors.lastname: Kuhn
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Bingshou
authors.initials: B
authors.lastname: Huang
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Yiping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Aijia
authors.initials: A
authors.lastname: Yu
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Walker
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Mark
authors.initials: M
authors.lastname: Niosi
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Larry
authors.initials: L
authors.lastname: Tremaine
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.).
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Medicine Design (H.G., R.E.K., Y.B., M.V.S.V., M.A.C., R.S., G.S.W., M.N., L.T., A.D.R.), and Nonclinical Statistics, Pfizer Inc., Groton, Connecticut (M.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (R. T., Y. A.); and WuXi AppTec, Waigaoqiao Free Trade Zone, Shanghai, China (B. H., Y. L., A.Y.) a.david.rodrigues@pfizer.com.
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D002460:Cell Line; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology*; D013431:Sulfates / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D027361:Organic Anion Transporters; D011804:Quinolines; D013431:Sulfates; C108475:pitavastatin; D012293:Rifampin