Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in 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.
Metabolism of Chemical Carcinogens by Intestinal Tissue
Herman Autrup, Gary M. Williams in Experimental Colon Carcinogenesis, 2019
Many compounds including widely used drugs are conjugated in the intestine mainly by glucuronidation.27,89 It is assumed that these conjugation reactions protect the body against any harmful compounds since the reaction products are easily excreted. Oxidized products usually undergo glucuronidation; but sulfate conjugates have also been isolated from the mucosal cells of rat small intestine.43 Sulfates, glucuronides, and glutathione conjugates of BP metabolites have been isolated from human colonic and duodenal expiant cultures, sulfate esters being predominant.90,91 High substrate concentrations favor glucuronidation as might be the case during drug therapy, while low concentrations favor sulfate conjugation.92 This latter situation might apply during exposure to environmental carcinogens.
Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
In humans, ~72% of the administered dose of lasofoxifene is recovered from the urine and feces, with majority of the dose excreted in the feces, probably via bile (Prakash et al. 2008). The absorption of lasofoxifene is slow, with Tmax values typically exceeding 6 h. The primary metabolic routes of lasofoxifene in humans are direct conjugation (glucuronide and sulfate conjugates) and Phase I oxidation, each accounting for approximately half of the metabolism (Prakash et al. 2008). The primary Phase I metabolites result from hydroxylations on the tetraline moiety and the phenyl rings attached to the tetraline and oxidation on the pyrrolidine moiety. The turnover of lasofoxifene is very slow in human liver microsomes, and only two metabolites are identified as two regioisomers of the catechol metabolite. Further in vitro experiments with recombinant CYPs and selective inhibitors suggested that the oxidative metabolism of lasofoxifene is catalyzed primarily by CYP3A and 2D6 (Prakash et al. 2008). In addition, its glucuronidation is catalyzed by multiple UGTs that are expressed in both the liver (UGT1A1, 1A3, A6, and 1A9) and the intestine (UGT1A8 and 1A10) (Prakash et al. 2008).
In vitro hepatic metabolism of the natural product quebecol
Published in Xenobiotica, 2023
Gabriel Bernardes, Ed S. Krol
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
Several antiepileptic drugs have been shown to undergo glucuronidation before excretion from the body. UGT1A isoforms catalyze the N-glucuronidation of several antiepileptic drugs. One of these is lamotrigine, a drug extensively metabolized predominantly by UGT1A4 and represents the only antiepileptic drug for which glucuronidation is known to strongly contribute to multidrug-resistance. As lamotrigine oral clearance is markedly increased (by >50%) by gestation and the use of estrogen-based oral contraceptives (Ohman et al. 2008; Reimers et al. 2011), further research has revealed that 17β-estradiol up-regulates the expression of UGT1A4 (Chen et al. 2009). Immunohistochemical analysis of temporal lobe resections of brains from epilepsy-suffering patients has revealed the high expression of UGT1A4 in neurons and endothelial cells of blood–brain barrier. The glucuronidation of lamotrigine was increased in drug-resistant human brain epileptic endothelial cells as compared to endothelial cells from non-pathological brains (Ghosh et al. 2013). Carbamazepine, an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain, is a known UGT inducer. Administration of this drug to Spraque-Dawley rats led to the induction of Ugt1a6 and Ugt1a7 mRNA; serotonin glucuronidation in the brain also increased (Asai et al. 2017). In healthy volunteers, co-administration of carbamazepine and vixotrigine, a neuropathic pain medication, caused reduction in AUC and Cmax of vixotrigine, although this effect was not considered clinically relevant (Dunbar et al. 2020).
Alitretinoin for the treatment of severe chronic eczema of the hands
Published in Expert Opinion on Pharmacotherapy, 2022
Maddalena Napolitano, Luca Potestio, Mario De Lucia, Mariateresa Nocerino, Gabriella Fabbrocini, Cataldo Patruno
The half-life of alitretinoin (t½) is 2–10 hours, while the time for the maximum plasma concentration is 2.5–4 hours [26]. Like other retinoids, alitretinoin is lipophilic and strongly bound to plasma lipoproteins (mean protein binding values of 99.0% in males 99.1% in females). Absolute bioavailability is unknown due to the absence of intravenous formulations [26]. Its metabolism starts in the gastrointestinal tract but is mainly hepatic and consists of oxidation and isomerization. The enzymes responsible for the metabolism of alitretinoin are cytochromes (CYP) P450 2C8, CYP P450 2C9, and CYP P450 3A4 (CYP3A4) [27]. The main metabolite of alitretinoin is 4-oxo-alitretinoin. Minor metabolites are 13-cis-RA, all-trans-RA, 4-oxo-all-trans-RA, and 4-oxo-9-cis-RA [27]. Following oral administration, more than 70% of the alitretinoin systemic exposure is formed by 4-oxo-alitretinoin. After glucuronidation, the metabolite is excreted in urine [14,23]. Elimination of other metabolites is complete in about 11 days, and mostly (63%) excreted in urine. Finally, pharmacokinetics of alitretinoin and its metabolites are similar between patients with cirrhosis and healthy controls; showing that alitretinoin can be administered also for such patients with a close follow-up [28].