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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Glucuronidation is an important detoxification pathway in humans. Many therapeutic drugs and their metabolites are substrates for UDP-glucuronyltransferases (UGT) leading to the formation of usually inactive glucuronides (a notable exception is morphine 6 glucuronide which has analgesic activity [9]) which are then eliminated via the bile or urine [10].
Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Its absorption after oral administration is complete. Glucuronidation is the main metabolic pathway. Lamotrigine and carbamazepine in combination can cause toxic levels of 10, 11-epoxide of carbamazepine in certain patients (Walker and Patsalos, 1995).
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Arylamine biotransformation provides an additional example of how dose and duration of exposure can influence the degree of toxicity. Sulfation, glucuronidation, and acetylation all result in electrophilic intermediates (Kadlubar and Beland, 1985). The acetylated and glucuronidated conjugates however, are more stable than the sulfated conjugate; therefore, acetylation and glucuronidation are considered detoxifying (Mulder, 1979). Acute exposures tend to lead to conjugation with the sulfate since it is a low-affinity, high-capacity system. As the dose increases, acetylation and glucuronidation tend to predominate since acetylation is an intermediate affinity and capacity system and glucuronidation is a low-affinity, high-capacity system. With chronic exposures, glucuronidation is favored since it is inducible and sulfation and acetylation are not.
In vitro hepatic metabolism of the natural product quebecol
Published in Xenobiotica, 2023
Glucuronidation is a well-known metabolism and detoxification pathway of drugs in humans which takes place predominantly in the liver (Yang et al. 2017). We determined the in vitro hepatic glucuronidation kinetic parameters of quebecol in pooled HLM (Table 1) to generate accurate data to predict in vivo human clearance. It is important to note that we followed our previous protocol for assessing glucuronidation kinetics in vitro (Lin et al. 2013) and did not include a detergent which can enhance UGT activity in vitro (Walsky et al. 2012). Since we were measuring the loss of substrate rather than metabolite formation, our time points were taken very early in the reaction to ensure linearity. We believe this should allow sufficient UGT activity as UDP-Glucuronic acid was present in excess. We note however that our results may be a lower estimate of activity and therefore clearance.
The role of UDP-glycosyltransferases in xenobioticresistance
Published in Drug Metabolism Reviews, 2022
Diana Dimunová, Petra Matoušková, Radka Podlipná, Iva Boušová, Lenka Skálová
Drug-resistance represents one of the major obstacles of current therapy, especially cancer therapy, leading to treatment failure. Studies by Cummings et al. (2002, 2004) have suggested that glucuronidation should be considered as a possible mechanism of drug-resistance. The reduced effectiveness of therapy is either due to inherent overexpression of an UGT enzyme (i.e. intrinsic drug-resistance), or due to drug- or another factor-induced enzyme expression (i.e. acquired drug-resistance). This induction often occurs via receptors (e.g. AhR) and other transcription factors. UGT-mediated drug-resistance has been studied in drugs used for epilepsy, psychiatric disorders, hypertension, hypercholesterolemia, and HIV infection treatment, although most efforts have been devoted to the study of drug-resistance to anticancer drugs (Colmegna et al. 2018; Osborne et al. 2019; Verma et al. 2019). The important role of UGTs in the drug-resistance of cancer cells has been described in excellent reviews (Kaur et al. 2020; Allain et al. 2020). The effect of UGT gene polymorphism in the development of intrinsic drug-resistance has also been summarized previously (Mazerska et al. 2016; Allain et al. 2020), therefore, only the acquired resistance to drugs for treatment of non-oncological diseases is discussed further here.
Species-dependent hepatic and intestinal metabolism of selective oestrogen receptor degrader LSZ102 by sulphation and glucuronidation
Published in Xenobiotica, 2022
David Pearson, Yi Jin, Andrea Romeo, Bertrand-Luc Birlinger, Hilmar Schiller, Yan Ji, Mithat Gunduz, Daniela Baldoni, Markus Walles
Sulphation and glucuronidation are common, related metabolic pathways, involving transfer of a hydrophilic sulphate or glucuronide group, often to an alcohol or carboxylic acid moiety (for glucuronides) as observed for LSZ102. Sulphation and glucuronidation reactions are catalysed by the SULT (Gamage et al. 2006) and UDP-glucuronosyltransferase (UGT) (King et al. 2000; Rowland et al. 2013) enzymes, respectively. Due to the similarity of the sulphation and glucuronidation reactions, many molecules are substrates of both enzyme families and form both sulphate and glucuronide metabolites. In particular, oestradiol and several oestrogen receptor targeting drugs have been identified to be substrates of sulphation and/or glucuronidation (Longcope et al. 1985; Falany et al. 2006; Hui et al. 2015). Similar to LSZ102, oestradiol is reported to be metabolised by both sulphation and glucuronidation, with a potential major intestinal first-pass effect (Longcope et al. 1985). Fulvestrant has been shown to be metabolised by glucuronidation and sulphation in human, but only sulphation was reported as a major pathway in rat and dog (Robertson and Harrison 2004). Raloxifene is estimated to be extensively metabolised in the intestine in rat and human (Kemp et al. 2002; Mizuma 2009; Matsuda et al. 2015). Similar to LSZ102, raloxifene contains the 6-hydroxybenzothiophene moiety, which is a site of glucuronidation and sulphation for both compounds. Glucuronidation has additionally been shown to be a major hepatic and intestinal metabolism pathway of a range of phenolic compounds (Wu et al. 2011).