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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Morphine is largely metabolised by UGT2B7 to morphine-6-glucuronide and morphine-3-glucuronide [9], and has been suggested as a probe substrate for this UGT isoform [86]. A number of in vivo studies have already been described on the development changes in morphine clearance in children [87–90].
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Selexipag is rapidly absorbed and is hydrolysed by CES1 in the liver to its active metabolite. Oxidative metabolism catalysed by CYP3A4 and CYP2C8 leads to the formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite.
Clinical pharmacology of opioids: opioid switching and genetic basis for variability in opioid sensitivity
Published in Nigel Sykes, Michael I Bennett, Chun-Su Yuan, Clinical Pain Management, 2008
Columba Quigley, Joy Ross, Julia Riley
A number of single nucleotide polymorphisms (SNPs) in the promoter region of UGT2B7 have been reported but their impact on enzyme function is debated.70In vitro studies demonstrate altered transcription factor binding to polymorphic regions, but these do not translate into altered promoter activity.71 Whilst one clinical study showed that genetic variation in the promoter region correlated with serum morphine and morphine-6-glucuronide concentrations,72 this was not confirmed in a subsequent larger study.73 One functional SNP in exon 2 results in an amino acid substitution, histidine to tyrosine, at the proposed location of the substrate binding site.71 However, Holthe et al.74 found no relationship between this variant and morphine metabolism in patients with cancer.
A potential paradigm shift in opioid crisis management: The role of pharmacogenomics
Published in The World Journal of Biological Psychiatry, 2022
David Eapen-John, Ayeshah G. Mohiuddin, James L. Kennedy
Morphine metabolism is mediated by the activity of UGT2B7. This process produces two major metabolites: morphine-3-glucuronide (M3G) which is an inactive metabolite accounting for about 60% of the original morphine dose, and morphine-6-glucuronide (M6G) which has higher analgesic activity than morphine and accounts for 5–10% of the original dose (Ning et al. 2019). Both metabolites are more hydrophilic than morphine and thus UGT2B7 glucuronidation accounts for about 66% of morphine excretion (Ning et al. 2019). Polymorphisms in UGT2B7 may affect both the activity of the enzyme overall and alter the proportion of M3G and M6G produced (Ning et al. 2019). The most well-studied polymorphism in this gene is C802T (rs7439366), and the variant T allele has been associated with significantly higher pain scores and plasma morphine concentrations in patients given equivalent morphine doses (Ning et al. 2019).
Selexipag for the treatment of pulmonary arterial hypertension
Published in Expert Review of Respiratory Medicine, 2021
Léon Genecand, Julie Wacker, Maurice Beghetti, Frédéric Lador
Hydroxylation of selexipag to its active metabolite ACT-333,679 is catalyzed in liver microsomes mainly by carboxylesterase 1, and to a small percentage by carboxylesterase 2 [37,38]. A small part of the hydroxylation of selexipag into ACT-333,679 might already take place in the intestine through human intestinal microsomes catalyzed by carboxylesterase 2 [38]. Cytochrome P450 (CYP) 3A4 and CYP2C8 also metabolize selexipag with oxidation and dealkylation reactions [37]. ACT-333,679 undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 1A3 and UGT2B7 [37]. As for selexipag, ACT 333,679 is also metabolized by CYP3A4 and CYP2C8 [37]. The excretion of selexipag, ACT-333,679 and their metabolic products are mostly biliary (approximately 90%) [39]. In vitro, selexipag and ACT-333,679 are weak substrates of OATP1B1 and OATP1B3 and selexipag is a weak substrate of the efflux pump P-Gp [40].
Comparison of the inhibition potential of parthenolide and micheliolide on various UDP-glucuronosyltransferase isoforms
Published in Xenobiotica, 2019
Wei-Feng Gao, Yi-Xuan Li, Wei-Hua Zhang, Ran Tao, Ting-Ting Yin, Yi-Jia Wang, Li-Na Liu, Zhi-Wei Fu, Sai-Nan Li, Nai-Rong Liu, Heng Zhang, Guang Liu, Li-Zhong Zhao, Xi-Peng Zhang, Chun-Ze Zhang
UDP-glucuronosyltransferases (UGTs) are one of the most important phase II DMEs, and have been demonstrated to participate in about 35% of all phase II reactions (Kiang et al., 2005). Phase II reactions can increase the polarity of the lipophilic substrate and make these molecules more amended for biliary and renal excretion (Sun et al., 2017). UGTs-catalyzed glucuronidation metabolism has been demonstrated to participate in the metabolic elimination of various drugs and drug candidates. For example, UGT2B7 catalyzes the glucuronidation metabolism of clinical drug epirubicin (Innocenti et al., 2001). Resveratrol can be effectively glucuronidated by UGTs expressed in human gastrointestinal tract (Sabolovic et al., 2010). UGTs have been also demonstated to catalyze the metabolism of many endogenous substances (Cao et al., 2017). For example, the glucuronidation conversion of thyroid hormone in the liver is mainly catalyzed by UGT1A1 and UGT1A3 (Kato et al., 2008). UGT2B15 and UGT2B17 catalyze the metabolism of androgen in the prostate gland (Chouinard et al., 2007). UGTs have been also reported to play an important role in the metabolism of bilirubin, bile acid and estradiol (Erichsen et al., 2010).Therefore, the activities of UGT isoforms are indispensable for maintaining the health of humans.