Leveraging of rifampicin-dosed cynomolgus monkeys to identify bile acid 3-O-sulfate conjugates as potential novel biomarkers for organic anion-transporting polypeptides s

Rhishikesh Thakare, Hongying Gao, Rachel E. Kosa, Yi An Bi, Manthena V.S. Varma, Matthew A. Cerny, Raman Sharma, Max Kuhn, Bingshou Huang, Yiping Liu, Aijia Yu, Gregory S. Walker, Mark Niosi, Larry Tremaine, Yazen Alnouti, A. David Rodrigues

Research output: Contribution to journalArticle

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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-free C max values (0.06, 0.66, 2.57, and 7.79 μM, respectively) spanning the reported in vitro IC 50 values for OATP1B1 and OATP1B3 (≤1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v. 2 H 4 -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 (≤100 μM) 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 (5 μM); 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.

Original languageEnglish (US)
Pages (from-to)721-733
Number of pages13
JournalDrug Metabolism and Disposition
Volume45
Issue number7
DOIs
StatePublished - Jul 2017

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Macaca fascicularis
Rifampin
Bile Acids and Salts
Sulfates
Anions
Biomarkers
Peptides
Taurochenodeoxycholic Acid
Taurodeoxycholic Acid
Deoxycholic Acid
Area Under Curve
Glycodeoxycholic Acid
Glycochenodeoxycholic Acid
Taurocholic Acid
Liver
Tandem Mass Spectrometry
Liquid Chromatography
Cytosol
Haplorhini
Hepatocytes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Leveraging of rifampicin-dosed cynomolgus monkeys to identify bile acid 3-O-sulfate conjugates as potential novel biomarkers for organic anion-transporting polypeptides s . / Thakare, Rhishikesh; Gao, Hongying; Kosa, Rachel E.; Bi, Yi An; Varma, Manthena V.S.; Cerny, Matthew A.; Sharma, Raman; Kuhn, Max; Huang, Bingshou; Liu, Yiping; Yu, Aijia; Walker, Gregory S.; Niosi, Mark; Tremaine, Larry; Alnouti, Yazen; Rodrigues, A. David.

In: Drug Metabolism and Disposition, Vol. 45, No. 7, 07.2017, p. 721-733.

Research output: Contribution to journalArticle

Thakare, R, Gao, H, Kosa, RE, Bi, YA, Varma, MVS, Cerny, MA, Sharma, R, Kuhn, M, Huang, B, Liu, Y, Yu, A, Walker, GS, Niosi, M, Tremaine, L, Alnouti, Y & Rodrigues, AD 2017, ' Leveraging of rifampicin-dosed cynomolgus monkeys to identify bile acid 3-O-sulfate conjugates as potential novel biomarkers for organic anion-transporting polypeptides s ', Drug Metabolism and Disposition, vol. 45, no. 7, pp. 721-733. https://doi.org/10.1124/dmd.117.075275
Thakare, Rhishikesh ; Gao, Hongying ; Kosa, Rachel E. ; Bi, Yi An ; Varma, Manthena V.S. ; Cerny, Matthew A. ; Sharma, Raman ; Kuhn, Max ; Huang, Bingshou ; Liu, Yiping ; Yu, Aijia ; Walker, Gregory S. ; Niosi, Mark ; Tremaine, Larry ; Alnouti, Yazen ; Rodrigues, A. David. / Leveraging of rifampicin-dosed cynomolgus monkeys to identify bile acid 3-O-sulfate conjugates as potential novel biomarkers for organic anion-transporting polypeptides s In: Drug Metabolism and Disposition. 2017 ; Vol. 45, No. 7. pp. 721-733.
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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-free C max values (0.06, 0.66, 2.57, and 7.79 μM, respectively) spanning the reported in vitro IC 50 values for OATP1B1 and OATP1B3 (≤1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v. 2 H 4 -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 (≤100 μM) 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 (5 μM); 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.",
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AU - Bi, Yi An

AU - Varma, Manthena V.S.

AU - Cerny, Matthew A.

AU - Sharma, Raman

AU - Kuhn, Max

AU - Huang, Bingshou

AU - Liu, Yiping

AU - Yu, Aijia

AU - Walker, Gregory S.

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AU - Rodrigues, A. David

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N2 - 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-free C max values (0.06, 0.66, 2.57, and 7.79 μM, respectively) spanning the reported in vitro IC 50 values for OATP1B1 and OATP1B3 (≤1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (i.v. 2 H 4 -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 (≤100 μM) 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 (5 μM); 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.

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