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Phenacemide
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
The aromatic hydroxylation reactions may occur by mechanisms that involve arene oxide metabolites (11). These intermediates are very reactive and may have substantial toxic potential by virtue of their ability to bind covalently to macromolecules. Such binding could result in direct cytotoxicity or in the formation of haptens that elicit immune responses (11). PAC has marked dose-dependent cytotoxicity over a concentration range of 11 to 178 pg/ml in an in vitro test system containing human lymphocytes and mouse microsomes (to generate arene oxide intermediates like those formed during PAC metabolism in vitro) (12). The toxic potential of PAC in vitro is greater than that of phenobarbital (PB) or PHT when each is present at its respective therapeutic concentration (12). Since PAC toxicity is likely to result from drug metabolites rather than the parent drug, variability in hepatic metabolism may be important in determining when and in whom PAC toxicity occurs. For example, drug therapy with PB might be expected to induce hepatic enzymes and thereby enhance the generation of arene oxide metabolites from concurrently administered PAC.
Overview of the Biotransformation of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Phenytoin is an active anticonvulsant drug and is effective for the treatment of seizures without biotransformation. Phenytoin is inactivated primarily by p-hydroxylation on one of the phenol groups attached to the 5 carbon. Oxidative enzymes in the liver promote the formation an arene oxide (epoxide) intermediate which rearranges nonenzymatically to form para- and meta-hydroxy metabolites. Quantitatively, the para-hydroxy metabolite accounts for as much as 90% of an administered dose of phenytoin, with only insignificant amounts of the meta derivative being formed. A very small amount of the arene oxide intermediate is hydrated by epoxide hydrolase to form a dihydrodiol that is further oxidized to a catechol, which is, in turn, methylated to form 3-O-methylcatechol. The arene oxide has not been isolated in humans. The hydantoin ring can be hydrolyzed to form trace amounts of di-phenylhydantoic acid. A dihydroxy metabolite, 5,5-bis (4-hydroxyphenyl) hydantoin, has been reported. The hydroxylated metabolites are conjugated with glucuronic acid and are excreted in urine. The O-glucuronidated metabolites are secreted into bile, but almost all of the conjugated drug is hydrolyzed in the gut and returned to the systemic circulation; little is eliminated in the feces. None of the biotransformation products of phenytoin have any significant antiepileptic activity.
Drug-induced eosinophilia and systemic symptoms
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Rajesh Verma, Pradeesh Arumugam
Anticonvulsants: Genetic polymorphisms that affect detoxification of anticonvulsants could be a cause [14]. The inability to detoxify toxic arene oxide metabolites is probably a key factor for the cross-reactivity between phenytoin, oxcarbazepine, and phenobarbital [17].
Identification of novel glutathione conjugates of terbinafine in liver microsomes and hepatocytes across species
Published in Xenobiotica, 2019
Amol Patil, Mayurbhai Kathadbhai Ladumor, Shyam H Kamble, Benjamin M. Johnson, Murali Subramanian, Michael W. Sinz, Dilip Kumar Singh, Sivaprasad Putlur, Priyadeep Bhutani, Deepak Suresh Ahire, Saranjit Singh
The second category includes metabolites formed by arene oxidation and GSH conjugate formation, with or without N-demethylation (M7, M9, M12, and M14 - M16). These metabolites were characterized by MS/MS product ions of m/z 495 and m/z 93 (or m/z 481 and m/z 93 in the case of N-desmethyl metabolites), indicating the conjugated side chain of TBF was unmodified and implicating the naphthalene motif of TBF as the site of attachment of GSH. The observation of multiple GSH conjugates of TBF in this category could be explained by the susceptibility of multiple sites toward arene oxidation and by the formation of two regioisomeric GSH conjugates for each discrete arene oxide intermediate. Naphthalene itself is known to react similarly when incubated with GSH- and NADPH-supplemented liver microsomes (Buckpitt et al., 1987), and arene oxide metabolites of compounds such as amitriptyline and duloxetine have been implicated previously in the onset of hepatotoxicity (Wen et al., 2008; Wu et al., 2010).
Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance?
Published in Drug Metabolism Reviews, 2018
Feng Chen, De-Yi Li, Bo Zhang, Jie-Yu Sun, Fang Sun, Xing Ji, Jin-Chun Qiu, Robert B. Parker, S. Casey Laizure, Jing Xu
CYP1A1/-A2 catalyzes the transformation of some therapeutic agents such as theophylline, olanzapine, tizanidine, and melatonin. For example, a larger proportion of participants in the diabetes group was found to be with the highly inducible CYP1A2 genotype, and accordingly, the CYP1A2 enzyme activity, as determined by caffeine metabolism was higher in the T2DM group (Urry et al. 2016). The CYP1A2 enzyme activity also mediated the oxygenation of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines/amides producing carcinogenic arene oxide, diolepoxide, and other electrophilic reactive species, which form DNA and protein adducts leading to tumor formation and toxicity (Ma and Lu 2007). Thus, diabetic patients exposed to tobacco smoke, automobile exhaust, and smoked food; they are particularly vulnerable to the metabolic activation of these carcinogenic chemicals by altered CYP1A enzymes.
Carbamazepine-induced renal toxicity may be associated with oxidative stress and apoptosis in male rat
Published in Drug and Chemical Toxicology, 2023
Elif Erdem Guzel, Nalan Kaya Tektemur, Ahmet Tektemur, Ebru Etem Önalan
Renal tubular cells, especially proximal tubule cells, are susceptible to the toxic effects of drugs due to their role in concentrating and reabsorbing glomerular filtrate (Naughton 2008). It has been shown that despite all nephron segments can be damaged through oxidative stress by assorted drugs, the tubules are a widespread target (Perazella 2019). In accordance, the reactive metabolite of CBZ known as arene oxide is well documented to be involved in oxidative stress as a mechanism for cellular injury triggered by this drug (Eghbal et al.2013). Therefore, our histopathological evaluations showed obvious kidney damage in CBZ-treated groups, including glomerular atrophy, inflammatory cell infiltration, degeneration of renal tubular epithelial cells, vacuolization, and hyaline cast formation in the tubule (Figure 1(a); B,C,D), which are generally commented as an indication of drug toxicity. Furthermore, CBZ treatment resulted in a significant increase in the frequency of tubular injuries such as intraepithelial vacuolization, tubular cell loss, and sloughed epithelial cells into the lumen, indicating that CBZ may also promote renal tubular cell damage. Moreover, it is known that oxidative stress promotes inflammation resulting in further tissue injury with aggregation of impaired biomacromolecules. Thus, we hypothesize that renal inflammatory infiltration may contribute to CBZ-induced renal toxicity. Based on these facts, the results of the histopathological findings showed that the possible time and dose-dependent disrupting potential of the CBZ drug on the histological structure of kidneys in rats. We further hypothesize that this reno-toxic effect of the drug on kidney histological features is due to oxidative stress as evidenced by the OSI results. Our findings are consistent with reports of Akorede (2020), Osuntokun et al. (2017), Hussien (2020), and Osuntokun et al. (2020); all of whom reported induced histopathological changes in testis after CBZ treatments in rodents via oxidative stress.