PT  - JOURNAL ARTICLE
AU  - Rhishikesh Thakare
AU  - Hongying Gao
AU  - Rachel E Kosa
AU  - Yi-An Bi
AU  - Manthena V.S. Varma
AU  - Matthew Cerny
AU  - Raman Sharma
AU  - Max Kuhn
AU  - Bingshou Huang
AU  - Yiping Liu
AU  - Aijia Yu
AU  - Gregory S Walker
AU  - Mark Niosi
AU  - Larry M Tremaine
AU  - Yazen Alnouti
AU  - A. David Rodrigues
TI  - Leveraging of Rifampicin-Dosed Cynomolgus Monkeys to Identify Bile Acid 3-O-Sulfate Conjugates as Potential Novel Biomarkers for Organic Anion-Transporting Polypeptides
AID  - 10.1124/dmd.117.075275
DP  - 2017 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.117.075275
4099  - http://dmd.aspetjournals.org/content/early/2017/04/10/dmd.117.075275.short
4100  - http://dmd.aspetjournals.org/content/early/2017/04/10/dmd.117.075275.full
AB  - 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 Cmax values (0.06, 0.66, 2.57 and 7.79 μM, respectively) that covered the reported in vitro IC50s for OATP1B1 and OATP1B3 (≤ 1.7 μM). As expected, the area under the plasma concentration-time curve (AUC) of an OATP probe drug (intravenous 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 also and it was 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). It is concluded that sulfated BAs may serve as sensitive biomarkers of cynomolgus monkey OATPs. Exploration of their utility as circulating human OATP biomarkers is warranted.