Warfarin is an Effective Modifier of Multiple UDP-Glucuronosyltransferase Enzymes: Evaluation of its Potential to Alter the Pharmacokinetics of Zidovudine

Sun, Hua; Zhang, Tianpeng; Wu, Zhufeng; Wu, Baojian

doi:10.1002/jps.24250

Cited by 16 publications

(15 citation statements)

References 52 publications

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“…Likewise, LCA has the potential to block the glucuronidation process in human gastrointestinal tract for many UGT substrates, and thus improve the oral bioavailability of many phenolic drugs or natural products. Particularly, for drugs with relatively high therapeutic index that are predominantly metabolized by UGTs, such as the anti-inflammatory agent, daphnetin (Liang et al, 2010), the cholagogue drug, armillarisin A (Sun et al, 2014), the anesthetic agent, propofol (Liang et al, 2011), and the antiretroviral agent, zidovudine (Sun et al, 2015), the co-administration of LCA may extend their half-life and subsequently increase their efficacy in vivo and also potentially reduce the treatment cost.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Hong

et al. 2016

Food and Chemical Toxicology

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Licochalcone A (LCA) is a major bioactive compound in Licorice, a widely used herbal medicine. In this study, the inhibitory effects of LCA against human UDP-glucuronosyltransferases (UGTs) and LCA associated herb-drug interactions were systematically investigated. Our results demonstrated that LCA displayed broad-spectrum inhibition against human UGTs. LCA exhibited strong inhibitory effects against UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A9, and 2B7 (both IC50 and Ki values lower than 5 μM), while showing moderate inhibitory effects against UGT1A8, 1A10, 2B4, 2B15, and 2B17. The inhibitory effects of LCA against two major UGTs, including UGT1A1 and 1A9, were further investigated in human liver microsomes (HLMs), where the potential risks of LCA via inhibition of UGT1A1 and 1A9 were predicted by combining the in vitro inhibitory data and physiological data. The results from this study also showed that several LCA-containing products were able to increase the area under the curve (AUC) of the substrates that were predominantly metabolized by UGT1A1 or 1A9. These findings together demonstrate that LCA has a potent and broad-spectrum inhibitory effect against most human UGTs and thus suggest that much caution should be exercised when high-dose LCA is co-administered with UGT substrates.

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Section: Discussionmentioning

confidence: 99%

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Hong

et al. 2016

Food and Chemical Toxicology

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“…A possible limitation of this estimation is the lack of consideration of warfarin accumulation in the liver. Studies with rats have shown liver warfarin levels are possibly 3-fold higher than that observed in plasma (Levy et al, 2003;Sun et al, 2015). The similarities in physiology between rats and humans suggest that warfarin accumulation in the liver possibly occurs in humans.…”

Section: Discussionmentioning

confidence: 99%

Stereospecific Metabolism ofR- andS-Warfarin by Human Hepatic Cytosolic Reductases

et al. 2017

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Coumadin (rac-warfarin) is the most commonly used anticoagulant in the world; however, its clinical use is often challenging because of its narrow therapeutic range and interindividual variations in response. A critical contributor to the uncertainty is variability in warfarin metabolism, which includes mostly oxidative but also reductive pathways. Reduction of each warfarin enantiomer yields two warfarin alcohol isomers, and the corresponding four alcohols retain varying levels of anticoagulant activity. Studies on the kinetics of warfarin reduction have often lacked resolution of parent-drug enantiomers and have suffered from coelution of pairs of alcohol metabolites; thus, those studies have not established the importance of individual stereospecific reductive pathways. We report the first steady-state analysis of - and-warfarin reduction in vitro by pooled human liver cytosol. As determined by authentic standards, the major metabolites were 9R,11S-warfarin alcohol for -warfarin and 9S,11S-warfarin alcohol for-warfarin. -warfarin ( 150 pmol/mg per minute, 0.67 mM) was reduced more efficiently than-warfarin ( 27 pmol/mg per minute, 1.7 mM). Based on inhibitor phenotyping, carbonyl reductase-1 dominated-and -warfarin reduction, followed by aldo-keto reductase-1C3 and then other members of that family. Overall, the carbonyl at position 11 undergoes stereospecific reduction by multiple enzymes to form the alcohol for both drug enantiomers, yet -warfarin undergoes reduction preferentially. This knowledge will aid in assessing the relative importance of reductive pathways for- and -warfarin and factors influencing levels of pharmacologically active parent drugs and metabolites, thus impacting patient dose responses.

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“…For example, indinavir, an HIV therapeutic drug, can significantly induce the elevation of unconjugated bilirubin in serum through inhibition of UGT1A1-mediated bilirubin glucuronidation 10 . Many compounds have been reported to exert inhibition potential towards UGT isoforms, such as warfarin 11 and arbidol…”

Section: Discussionmentioning

confidence: 99%

Comparison of the inhibition capability of oleanolic acid and betulinic acid towards drug-metabolizing enzymes

Xiao

2015

Afr H. Sci.

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Background: Human UDP-glucuronosyltransferases (UGTs) are important membrane proteins located in endoplasmic reticulum, and play important roles in metabolism of a variety of endogenous and exogenous compounds. Aims: To determine the influence of subtle difference in the structure of oleanolic acid and betulinic acid towards the inhibition towards the activity of UGT isoforms. Methods: In vitro glucuronidation of 4-methylumbelliferone (4-MU) reaction was employed as the probe reaction to determine the inhibition of these two compounds towards UGTs' activity. Results: The inhibition of capability of oleanolic acid towards UGT1A6 and UGT1A8 were higher than betulinic acid. However, no significant difference was observed for the inhibition of oleanolic acid and betulinic acid towards UGT1A7. Furthermore, concentration-dependent behaviour was determined for the inhibition of oleanolic acid and betulinic acid towards UGT1A6 and UGT1A8. At various concentrations of oleanolic acid and betulinic acid, the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 was higher than betulinic acid. Conslusion: Given that UGT1A6 and UGT1A8 play key role in the the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 will induce drug-drug interaction and the risk of diseases.

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Warfarin is an Effective Modifier of Multiple UDP-Glucuronosyltransferase Enzymes: Evaluation of its Potential to Alter the Pharmacokinetics of Zidovudine

Cited by 16 publications

References 52 publications

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Stereospecific Metabolism ofR- andS-Warfarin by Human Hepatic Cytosolic Reductases

Comparison of the inhibition capability of oleanolic acid and betulinic acid towards drug-metabolizing enzymes

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