Lipid Modulation and Liver Function Tests: A Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH)

Buchwald, Hēnry; Williams, Stanley; Matts, John P.; Boen, James R.

doi:10.1177/174182670200900203

Cited by 3 publications

(2 citation statements)

References 20 publications

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“…It is well known that UGT1A1 is a detoxifying enzyme that also catalyzes glucuronic acid to conjugate many therapeutic drugs [27][28][29]. An increase in the total bilirubin concentration in participants who were treated with statin drugs has been reported [30,31]. Grosser et al reported that both aspirin and statin contribute to the induction of HO-1 [32,33].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease

Hsieh

Chen

Liao

et al. 2008

Cellular and Molecular Biology Letters

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Abstract:Bilirubin, an antioxidant in the blood, plays a role in protection from atherosclerosis. The level of bilirubin is highly correlated to the incidence of coronary artery disease (CAD). Unconjugated bilirubin is conjugated with glucuronic acid through the reaction of uridine 5'-diphosphate-glucuronosyl transferase 1A1 (UGT1A1). The interactions of CAD and the variations in the coding regions of the UGT1A1 gene have never been evaluated. The purpose of this study was to analyze the influence of the UGT1A1 variant on the incidence of CAD. There were 135 participants in this study: 61 in the experimental group, who had CAD, and 74 in the control group, who did not have CAD. The blood samples from all 135 participants were collected and assayed to clarify the relationship between bilirubin and CAD. The assay of the polymerase chain reaction and the sequence of the UGT1A1 gene were examined to find the gene's polymorphisms. The bilirubin levels for the participants in the control group were significantly higher than for the patients in the CAD group. Although the concentration of bilirubin in the UGT1A1 variant was higher than the wild type for the patients in the CAD group, there was no significant difference in the polymorphism of UGT1A1 between the patients in the CAD group and the participants in the control group.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease

Hsieh

Chen

Liao

et al. 2008

Cellular and Molecular Biology Letters

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“…Employing this approach, the oral bioavailability of acyclovir was enhanced in rats via a bile acid conjugate prodrug of acyclovir (Tolle-Sander et al, 2004). Furthermore, hASBT is a promising pharmacological target, where hASBT inhibitors could lower blood cholesterol (Buchwald et al, 2002). Hence, hASBT is a target for novel substrates and inhibitors.…”

Section: Impurity Impact On Kinetic Estimates 301mentioning

confidence: 99%

Impact of Impurity on Kinetic Estimates from Transport and Inhibition Studies

González

Polli²

2008

J Pharmacol Exp Ther

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Although in vitro transport/inhibition studies are commonly performed on impure drug candidates to screen for pharmacokinetic properties in early development, quantitative guidelines concerning acceptable impurity levels are lacking. The broad goal was to derive models for the effect of impurity on transport and inhibition studies and identify the maximum allowable impurity level that does not bias assay results. Models were derived, and simulations were performed to assess the impact of impurity on substrate properties K t and J max and inhibition K i . Simulation results were experimentally challenged with a known amount of impurity, using the intestinal bile acid transporter as a model system. For substrate uptake studies, glycocholate served as substrate and was contaminated with either a very strong, strong, or moderate impurity (i.e., taurolithocholate, chenodeoxycholate, or ursodeoxycholate, respectively). For inhibition studies, taurocholate and glycocholate together was the substrate/inhibitor pair, where glycocholate was contaminated with taurolithocholate. There was high agreement between simulation results and experimental observations. It is not surprising that, in the inhibition assay, potent impurity caused test compound to appear more potent than the true potency of the test compound (i.e., reduced inhibitory K i ). However, results in the transport scenario surprisingly indicated that potent impurity did not diminish test compound potency but, rather, increased substrate potency (i.e., reduced Michaelis-Menten substrate K t ). In general, less than 2.5% impurity is a reasonable target, provided the impurity is less than 10-fold more potent than test compound. Study results indicate that careful consideration of possible impurity effect is needed when quantitative structureactivity relationship analysis cannot explain high compound potency from transport or inhibition studies.Transport and inhibition studies are routinely performed in early development to screen for absorption, distribution, metabolism, and excretion (ADME). For example, a current project in our laboratory concerns the targeting of an intestinal transporter for drug delivery purposes (Balakrishnan and Polli, 2006). The transporter is the human apical sodium-dependent bile acid transporter (hASBT). ADME considerations in this project motivate the screening for substrates and inhibitors of hASBT to construct a quantitative structure-activity relationship (QSAR) model for inhibitors and substrates of this transporter. Test compounds are currently being synthesized to evaluate the chemical structural features that allows for hASBT inhibition, as well as translocation by hASBT (Balakrishnan et al., 2006a).However, test compounds in early development often contain chemical impurities, including intermediates that bear structural similarity to the target test compound. The presence of such impurities has potential to affect the results of pharmacologic assays, including ADME screening results. Guidelines on compound purity are n...

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Incidental biliary dilation in the era of the opiate epidemic: High prevalence of biliary dilation in opiate users evaluated in the Emergency Department

Barakat¹,

Banerjee²

2020

WJH

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Lipid Modulation and Liver Function Tests: A Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH)

Cited by 3 publications

References 20 publications

Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease

Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease

Impact of Impurity on Kinetic Estimates from Transport and Inhibition Studies

Incidental biliary dilation in the era of the opiate epidemic: High prevalence of biliary dilation in opiate users evaluated in the Emergency Department

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