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Critical care, neurology and analgesia
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Glucuronide metabolism occurs in the liver. An adult clearance of 20 ml/min/kg and Vss of 2.8 1/kg is reported [200]. Clearance in children (4–7 years) is higher than those in adults with similar Vss [209]. Buprenorphine clearance was 0.0138 ml/min/kg (SD 0.0042), the elimination half-life was 20 h (SD 8) and the volume of distribution was 6.2 1/kg (SD 2.11) in premature neonates [210].
Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Although normally safe in therapeutic doses, acute overdoses of acetaminophen (APAP) are associated with hepatotoxicity, which is often accompanied by acute renal failure (Kaloyanides, 1991). Renal toxicity is associated with proximal tubular necrosis that is dependent on metabolism of APAP by cytochrome P-450 to a reactive arylating species (Figure 3). The predominant metabolic pathway under pharmacological conditions is detoxification by glucuronide or sulfate conjugate formation. Under toxicological conditions, however, APAP is hydroxylated by P-450 to N-hydroxy APAP, which is chemically unstable and rearranges to the ultimate nephrotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI can react with GSH and be detoxified by the mercapturic acid pathway, or it can react with protein sulfhydryl groups to produce nephrotoxicity. Prior depletion of cellular GSH concentrations potentiates APAP-induced cytotoxicity, whereas increasing the cellular GSH concentrations, such as by addition of N-acetylcysteine, protects against injury, demonstrating the importance of this pathway in APAP metabolism.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The synthesis of the mono- and diglucuronides occurs mainly in the liver catalyzed by the microsomal enzyme uridine 5ˊ-diphosphate glucuronyltransferase (UDPGT).135,136,276 Conjugation is a prerequisite for the excretion of bilirubin into the bile and may itself be the limiting factor in transport, since conjugated bilirubin is excreted in the bile more rapidly than the unconjugated pigment. Conjugate formation occurs in kidney, intestines, lung, and skin. The renal cortex and the gastrointestinal mucosa contain UDPGT and a microsomal nicotinamide adenine dinucleotide-dependent oxidative enzyme which catalyzes bilirubin conjugation in a manner similar to hepatic microsomes. In the liver of the embryo and newborn, UDPGT levels are very low. However, in the gastrointestinal tract in the early fetal period this enzyme is present at adult levels. The inadequate synthesis of bilirubin conjugates in the human neonatal liver is responsible for the physiologic jaundice of the newborn. In contrast, various glucuronides, including glucuronides of injected foreign substances, are formed in the gastrointestinal tract, so this site may be important in the detoxication mechanism of the neonate.129 The regulation of glucuronide formation depends on many factors10,223,442 (Figure 20).
A host–gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood–brain barrier integrity in vivo
Published in Tissue Barriers, 2023
Andrew V. Stachulski, Tobias B-A Knausenberger, Sita N. Shah, Lesley Hoyles, Simon McArthur
Glucuronidation is a key stage in phase II metabolism and clearance of endogenous and exogenous molecules and has long been investigated in this regard. Much is now known about the various UDP-glucuronosyltransferases responsible for glucuronidation at different sites in the body,19 but the biological actions of glucuronide compounds once they have been formed are rather less understood. In most cases, glucuronide conjugates have been considered as biologically inactive and simply destined for renal elimination, but our data add to the steadily building picture that this may not be universally true. Notably, glucuronide derivatives of morphine, ethanol and estradiol have been shown to act as agonists of the TLR4 complex, promoting allodynia and inflammation upon spinal cord administration.20–22 Our data add the tyrosine/phenylalanine metabolite pCG to the list of glucuronide conjugates that can interact with TLR4 signaling, but with the marked difference that, in contrast to the other known activating agents, pCG is a functional antagonist and prevents the permeabilizing effects of bacterial endotoxin exposure upon the BBB.
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
Species differences in metabolism can result in disproportionately abundant human metabolites that require toxicity evaluation during clinical development (ICH 2009, 2010). As a result of the observed species difference in metabolism, some of the major human metabolites of LSZ102 were more abundant in human than in rat, which was a species used for toxicology studies of LSZ102. However, none of these metabolites are considered a safety risk, as all are phase II conjugative metabolites (glucuronide or sulphate) which are generally considered safe (ICH 2009; FDA 2016). Additionally, toxicological evaluations of metabolites are generally not considered relevant for terminal cancer indications (ICH 2010). Acyl-glucuronides have been associated with reactive metabolite formation, but an evaluation of the reactivity of acyl-glucuronide M6 in phosphate buffer showed that it has low reactivity (data not shown) similar to other acyl-glucuronides that are not associated with toxicity (Sawamura et al. 2010). Additionally, there remains no clear evidence that acyl-glucuronide reactivity is associated with toxicity (Walles et al. 2020).
Pharmacokinetics, metabolism, and excretion of licogliflozin, a dual inhibitor of SGLT1/2, in rats, dogs, and humans
Published in Xenobiotica, 2021
Lydia Wang-Lakshman, Anisha E. Mendonza, Roland Huber, Markus Walles, YanLing He, Venkateswar Jarugula
Pharmacokinetics of licogliflozin or its metabolites, may, however, also be impacted in patients with hepatic impairment as well as renal impairment. In fact, the direct glucuronide metabolites were mainly eliminated via renal excretion in humans. It is conceivable that in patients with decreased renal function, renal elimination of these glucuronides would be reduced, resulting in increased exposure to these metabolites. An exploratory assessment of the glucuronide metabolites in patients with decreased renal function indeed showed that while exposure levels to the glucuronide metabolites were found to be similar between patients with mild renal impairment and healthy subjects, an increase in exposure to the glucuronide metabolites was observed in patients with moderate (eGFR 30–59 mL/min/1.73m2) to severe (eGFR ≤ 29 mL/min/1.73m2, not on dialysis) renal impairment (RI) when compared to those in subjects with normal renal function. The highest exposure to M17 and M27 was observed in patients with severe RI where increases of ∼6- and ∼3-fold over exposure in normal subjects were observed (Unpublished data).