55547-48-3Relevant academic research and scientific papers
Leveraging of rifampicin-dosed cynomolgus monkeys to identify bile acid 3-O-sulfate conjugates as potential novel biomarkers for organic anion-transporting polypeptidess
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
supporting information, p. 721 - 733 (2017/06/27)
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) spanning the reported in vitro IC50 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.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 (≤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.
Hard Acid and Soft Nucleophile System. 2.Demethylation of Methyl Ethers of Alcohol and Phenol with an Aluminum Halide-Thiol System
Node, Manabu,Nishide, Kiyoharu,Fuji, Kaoru,Fujita, Eiichi
, p. 4275 - 4277 (2007/10/02)
Aliphatic and aromatic methyl ethers have been easily cleaved on treatment with a hard acid, aluminum halide, and a soft nucleophile, EtSH, to give parent alcohols and phenols, respectively.With compounds possessing both aliphatic and aromatic methyl ether groups, simultaneous demethylation of both types of ethers occurred.The ethereal carbon-oxygen bond in compounds possessing both ether and ester groups was selectively cleaved under mild conditions by using dichloromethane as a cosolvent.Acetoxyl and N-acetyl groups were shown to be stable to this reagent system, except for easy hydrolysis of aromatic acetoxyl groups under conditions of workup after the reaction.
