Rashim Singh
University of Houston
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Featured researches published by Rashim Singh.
Molecular Pharmaceutics | 2009
Haiyan Xu; Kaustubh H. Kulkarni; Rashim Singh; Zhen Yang; Stephen W. J. Wang; Vincent H. Tam; Ming Hu
The purposes of this study were to investigate how efflux transporters and UDP-glucuronosyltransferases (UGT) affect the disposition of naringenin. A rat intestinal perfusion model with bile duct cannulation was used along with rat intestinal and liver microsomes. In the intestinal perfusion model, both absorption and subsequent excretion of naringenin metabolites were rapid and site-dependent (p < 0.05). Naringenin was absorbed the most in colon, and its glucuronides were excreted the most in duodenum. In metabolism studies, the intrinsic clearance value of naringenin glucuronidation was the highest in jejunum microsomes, followed by liver, ileal and colonic microsomes. The rapid metabolism in microsomes did not always translate into more efficient excretion in the rat perfusion model, however, because of presence of rate-limiting efflux transporters. When used separately, MK-571 (an inhibitor of multidrug resistance-related protein 2 or Mrp2) or dipyridamole (an inhibitor of breast cancer resistance protein or Bcrp1) did not affect excretion of naringenin glucuronides, but when used together, they significantly (p < 0.05) decreased intestinal and biliary excretion of naringenin glucuronides. In conclusion, efflux transporters Mrp2 and Bcrp1 are shown to compensate for each other and enable the intestinal excretion of flavonoid (i.e., naringenin) glucuronides.
Journal of Pharmacology and Experimental Therapeutics | 2011
Baojian Wu; John Kenneth Morrow; Rashim Singh; Shuxing Zhang; Ming Hu
Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., Km, Vmax, intrinsic clearance (CLint) = Vmax/Km] derived for flavonols. This article aims to construct position (3-OH)-specific comparative molecular field analysis (CoMFA) models to describe UDP-glucuronosyltransferase (UGT) 1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized, and kinetic parameters (Km, Vmax, CLint) were obtained. The observed Km, Vmax, and CLint values of 3-O-glucuronidation ranged from 0.04 to 0.68 μM, 0.04 to 12.95 nmol/mg/min, and 0.06 to 109.60 ml/mg/min, respectively. To model UGT1A9-mediated glucuronidation, 30 flavonols were split into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to specific common feature pharmacophores, which were used to construct CoMFA models of Vmax and CLint, respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities (Vmax model: q2 = 0.738, r2 = 0.976, rpred2 = 0.735; CLint model: q2 = 0.561, r2 = 0.938, rpred2 = 0.630). The contour maps derived from CoMFA modeling clearly indicate structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9.
Drug Metabolism Reviews | 2017
Guangyi Yang; Shufan Ge; Rashim Singh; Sumit Basu; Katherine Shatzer; Ming Zen; Jiong Liu; Yifan Tu; Chenning Zhang; Jinbao Wei; Jian Shi; Lijun Zhu; Zhongqiu Liu; Yuan Wang; Song Gao; Ming Hu
Abstract Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.
Journal of Pharmaceutical and Biomedical Analysis | 2018
Changhong Yun; Wan Mohaiza Dashwood; Lawrence N. Kwong; Song Gao; Taijun Yin; Qinglan Ling; Rashim Singh; Roderick H. Dashwood; Ming Hu
HighlightsThe colon PGE2 of normal (wild type) rat and Pirc rat (an Apc‐mutant rat) were firstly accurately determined by specific and sensitive UPLC–MS/MS.PGE2 was confirmed to promote Pirc rat colon polyps.An optimized mobile phase (0.1% ammonia hydroxide) was found to greatly improve the chromatographic separation of prostaglandins. ABSTRACT An accurate and reliable UPLC–MS/MS method is reported for the quantification of endogenous Prostaglandin E2 (PGE2) in rat colonic mucosa and polyps. This method adopted the “surrogate analyte plus authentic bio‐matrix” approach, using two different stable isotopic labeled analogs — PGE2‐d9 as the surrogate analyte and PGE2‐d4 as the internal standard. A quantitative standard curve was constructed with the surrogate analyte in colonic mucosa homogenate, and the method was successfully validated with the authentic bio‐matrix. Concentrations of endogenous PGE2 in both normal and inflammatory tissue homogenates were back‐calculated based on the regression equation. Because of no endogenous interference on the surrogate analyte determination, the specificity was particularly good. By using authentic bio‐matrix for validation, the matrix effect and exaction recovery are identically same for the quantitative standard curve and actual samples – this notably increased the assay accuracy. The method is easy, fast, robust and reliable for colon PGE2 determination. This “surrogate analyte” approach was applied to measure the Pirc (an Apc‐mutant rat kindred that models human FAP) mucosa and polyps PGE2, one of the strong biomarkers of colorectal cancer. A similar concept could be applied to endogenous biomarkers in other tissues.
Molecular Pharmaceutics | 2009
Lan Tang; Rashim Singh; Zhongqiu Liu; Ming Hu
Molecular Pharmaceutics | 2010
Lan Tang; Ling Ye; Rashim Singh; Baojian Wu; Chang Lv; Jie Zhao; Zhongqiu Liu; Ming Hu
Journal of Pharmaceutical and Biomedical Analysis | 2010
Zhen Yang; Wei Zhu; Song Gao; Haiyan Xu; Baojian Wu; Kaustubh H. Kulkarni; Rashim Singh; Lan Tang; Ming Hu
Journal of Agricultural and Food Chemistry | 2010
Rashim Singh; Baojian Wu; Lan Tang; Zhongqiu Liu; Ming Hu
Journal of Agricultural and Food Chemistry | 2011
Rashim Singh; Baojian Wu; Lan Tang; Ming Hu
Molecular Pharmaceutics | 2012
Shengnan Meng; Baojian Wu; Rashim Singh; Taijun Yin; John Kenneth Morrow; Shuxing Zhang; Ming Hu