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The gastrointestinal tract
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Two related disorders of different severity caused by variants in the same gene encoding the transferase, UDP-glucuronosyltransferase (UDPGT): Gilbert's syndrome: A mild autosomal dominant trait, a harmless condition that is so common (around 5% of the population) it should be considered a normal variant rather than a diseaseDefective bilirubin conjugation (Crigler-Najjar syndrome): A complete absence of the transferase in type 1 (autosomal recessive) and a partial absence in type 2 (autosomal dominant)
Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
Ataluren (PTC124, Translarna™) is an oxadiazole of which the chemical structure is depicted in Figure 14.4. The drug is taken as an oral suspension and is metabolized by uridine diphosphate glucuronosyltransferase (UGT) enzymes in the liver into ataluren-O-1β-acyl glucuronide with (i) a tissue half-life of 2–6 hours, (ii) peak plasma levels being reached around 1.5 hours after administration, and (iii) 99.6% bound to plasma proteins (53). Ataluren was initially developed to treat Duchene muscular dystrophy (DMD) (54), for which it has been authorized in the European Union (53), but also seemed to be effective in clinical studies in individuals with CFTR premature termination mutations (55–57). The mechanism of action of Ataluren is not completely understood. It promotes translational read-through by stimulating insertion of near-cognate tRNAs at the premature termination codon with specific codon-anticodon preference for amino acid substitutions, for which direct binding to ribosomes seems to be required (58). The sequence surrounding the premature termination codon also seems to be important for this selection (59).
SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
Gilbert syndrome is an autosomal recessive inherited metabolic disorder (although occasionally inherited in an autosomal dominant fashion depending on the type of mutation), causing increased levels of unconjugated bilirubin in the blood. It is a common hereditary cause of hyperbilirubinaemia. There is decreased activity of the enzyme glucuronyltransferase, which conjugates bilirubin in the liver. Bilirubin is excreted from the body only in the conjugated form. Typical presentation is painless jaundice during an intercurrent illness.
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).
Pharmacokinetics of trastuzumab deruxtecan (T-DXd), a novel anti-HER2 antibody-drug conjugate, in HER2-positive tumour-bearing mice
Published in Xenobiotica, 2020
Hiromi Okamoto, Masataka Oitate, Katsunobu Hagihara, Hideyuki Shiozawa, Yoshitake Furuta, Yusuke Ogitani, Hiroshi Kuga
Moreover, the negligible metabolism of DXd, particularly the lack of glucuronidation or oxidation, is also a major advantage of T-DXd from the viewpoint of drug-drug interaction. For example, the toxicity of irinotecan (one of the commonly used topoisomerase I inhibitors) correlates with the polymorphism of the glucuronosyltransferase (UGT) 1A1 gene, because it is metabolised by the UGT1A1 enzyme via glucuronidation and excreted via bile (Iyer et al., 1998; Jinno et al., 2003). Therefore, UGT1A1 gene polymorphism limits the use of irinotecan owing to individual differences in the occurrence of adverse effects (Sai et al., 2008). In contrast, the fact that most of the DXd in this study was excreted intact (Figure 6(B) and Table 4) suggests that the contribution of glucuronidation to DXd elimination is minimal. These data are supported by the previous report of [14C]DXd excretion in bile duct-cannulated rat (Nagai et al., 2019). Hence, T-DXd would pose a minimal risk of adverse effects caused by such inter-individual differences in drug-metabolising enzymes. In addition, T-DXd is expected to have a low potential for drug-drug interactions with cytochrome P450 inhibitors, because the contribution of oxidation to the elimination of DXd is also minimal.
Combined repeated-dose and reproductive/developmental toxicity screening test of benzene, 1,1′-oxybis-, tetrapropylene derivs. in rats
Published in Drug and Chemical Toxicology, 2018
Yasuhiro Tsubokura, Ryuichi Hasegawa, Sunao Aso, Toshio Kobayashi, Takayuki Koga, Satsuki Hoshuyama, Yutaka Oshima, Katsumi Miyata, Yuji Kusune, Takako Muroi, Naoki Hashizume, Yoshiyuki Inoue, Shozo Ajimi, Kotaro Furukawa
In addition to the drug-inducible rat liver enzymes, CYP2B and CYP3A, chemicals including phenobarbital and pregnenolone-16α-carbonitrile, also induce a UDP-glucuronosyltransferase 2B (UGT2B) family, whose induction causes increased glucuronidation of triiodothyronine (T3) in the liver, leading to a decrease in T3 blood levels (Klaassen and Hood 2001, Richardson and Klaassen 2010). T3 reduction stimulates secretion of thyroid-stimulating hormone through the central nervous system, leading to thyroid gland hypertrophy and increased thyroid gland weight. In this study, hypertrophy of the follicular cells in the thyroid gland occurred in both sexes. Therefore, BOTD may be a CYP2B or CYP3A inducer, although the possibility that it induces another enzyme type related to nuclear factor erythroid 2-related factor 2 cannot be excluded, because the latter type is also a UGT2B family–specific inducer (Shelby and Klaassen 2006). An examination of the induction profile of hepatic drug-metabolizing enzymes is needed to determine which enzyme type BOTD induces.