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Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Conjugation of xenobiotic or endogenous compounds with glucuronic acid requires the microsomal enzyme UDP-glucuronosyltransferase (UDPGT). The aglycones that serve as substrates for UDPGT include hydroxyl (phenolic and alcoholic), carboxyl, sulfhydryl, and amino compounds and the glucuronic acid moiety is derived from UDP-glucuronic acid (UDPGA). Bilirubin, thyroxine, and steroid hormones are important endogenous substrates for UDPGT (Anders, 1980). Generally, glucuronide conjugation represents a detoxification pathway leading to more rapid elimination. However, certain glucuronides of yV-hydroxy compounds such as N-hydroxy-2-acetylaminofluorene and N-hydroxy-phenacetin are more reactive than the parent compound.
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 jaundice is due to defective conjugation caused by the delayed or absent development of the UDP-glucuronyltransferase or to inhibitory substances. These substances include various steroids, novobiocin, and male fern extract.236,237,261
Adrenergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Silodosin is an α1A subtype selective adrenoceptor antagonist utilized for treating BPH accompanied by little impact on BP. Rapid absorption with 32% bioavailability can be observed succeeding oral administration. It is 95.6% bound to protein specifically with AGP. Metabolism is by several pathways and the main metabolites produced are alcohol dehydrogenase (ADH/ALDH) via UDP-glucuronosyltransferase. Adverse effects include dizziness, orthostatic hypotension and the main adverse effect is retrograde ejaculation (Gugger, 2011; Matsubara et al., 2006; Michel, 2010; Montorsi, 2010; Rossi et al., 2010).
Palmitoylethanolamide: A Potential Alternative to Cannabidiol
Published in Journal of Dietary Supplements, 2023
Paul Clayton, Silma Subah, Ruchitha Venkatesh, Mariko Hill, Nathasha Bogoda
In studies assessing CBD’s pharmacokinetic parameters, high intra- and inter-subject variability make it difficult to definitively characterize its pharmacokinetics in both humans and animals (110, 111). Such processes are affected by differing drug formulations, routes of administration and extent of drug exposure in subjects (110). Challenges are also posed by rapid metabolism, reduced drug recovery due to adsorption of compounds to multiple surfaces, low analyte concentration and reduced separation of compounds (110). CBD has a low oral bioavailability (13–19%) (111, 112) due to high first-pass metabolism by the liver and extrahepatic tissue (110, 111). While being primarily metabolized by cytochrome P450 (CYP) enzymes, it may also be glucuronidated by several UDP-glucuronosyltransferase (UGT) isoforms (113). Its metabolites are mainly excreted by the kidneys (111) and eliminated in the feces, urine, sweat, oral fluid and hair (110). A large proportion of CBD is excreted unchanged in the feces (110).
Pharmacotherapeutic considerations for elderly patients with colorectal cancer
Published in Expert Opinion on Pharmacotherapy, 2019
FFCD 2001–02 evaluated untreated mCRC elderly patients randomly assigned to 5-FU vs. reduced starting dose irinotecan plus 5-FU [73,74]. PFS was longer in the irinotecan group but was not statistically significant and no difference was seen with OS [73]. A subanalysis looked at GAs [74]. Geriatric tools used MMSE, IADL, and GDS. No geriatric parameter was predictive for response or PFS. Normal IADL was independently associated with better OS. MMSE and IADL were predictive of severe toxicity or unexpected hospitalization (MMSE). Irinotecan when considered in the elderly we recommend a thorough DDI review, FFCD trial dose adjustment considerations given potential PK changes, and careful monitoring to determine dose escalation, dose reduction, or elimination of irinotecan along with the fluoropyrimidine considerations above. Maintenance therapy (eliminating irinotecan) should be considered at 4 months with first-line therapy. Patients with severe hepatic impairment (total bilirubin ≥ 3 mg/dl) should not be offered irinotecan and those with total bilirubin > ULN but <3 mg/dl when utilized should have substantial dose reductions. Testing considerations for UDP glucuronosyltransferase 1 member A1 should be performed for those considered high risk prior to use (i.e. frail, hepatic impairment, baseline diarrhea/fluid imbalance) to avoid extreme toxicity.
Glucuronidation of icaritin by human liver microsomes, human intestine microsomes and expressed UDP-glucuronosyltransferase enzymes: identification of UGT1A3, 1A9 and 2B7 as the main contributing enzymes
Published in Xenobiotica, 2018
Li Wang, Xiaodan Hong, Zhihong Yao, Yi Dai, Guoping Zhao, Zifei Qin, Baojian Wu, Frank J. Gonzalez, Xinsheng Yao
Glucuronidation is one of the most significant phase II conjugation reactions (Wu et al., 2011). Generally, it is a detoxification mechanism because the glucuronide is usually pharmacologically inactive and rapidly eliminated from the body due to its highly polar nature (Ritter, 2000). Meanwhile, it accounts for the clearance of ∼35% drugs metabolized by phase II enzymes (Evans & Relling, 1999). The mechanism of glucuronidation reaction is that a glucuronic acid derived from the cofactor uridine diphosphoglucuronic acid (UDPGA) is transferred to the substrate, generating the glucuronidated metabolite (or glucuronide) via the action of the UDP-glucuronosyltransferase enzymes (UGTs) (Sun et al., 2015). Human UGT enzymes are systematically classified into four subfamilies, UGT1, UGT2, UGT3 and UGT8 (Mackenzie et al., 2005). Usually, the UGT1A and 2B enzymes contribute significantly to metabolism and detoxification of xenobiotics (Lu et al., 2016). The UGT1A family contains nine members (i.e. UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9 and 1A10), whereas the UGT2B family contains seven members (i.e. UGT2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28).