Carbamazepine-Provoked Hepatotoxicity and Possible Aetiopathological Role of Glutathione in the Events

Abstract

The antiepileptic drug (AED) carbamazepine is widely used in the treatment of different kinds of seizures as well as affective and behavioural disorders. This paper presents an epidemiological study of carbamazepine-induced hepatic injuries and death, and describes the possible mechanisms of its toxicity. A retrospective analysis of clinical data revealed that the likelihood of hepatic death was comparatively higher in children, particularly when they were receiving medication with multiple AEDs, whereas reversible hepatic injuries were more likely to be seen in elderly patients. As suggested in this paper, the development of carbamazepine hepatotoxicity is rare, and unpredictable with the present state of knowledge, but it is somehow related to disturbance of glutathione metabolism, although data in this regard are imperfect. There appear to be two types of carbamazepine-initiated idiosyncratic liver injury, hypersensitivity and toxin-induced. It is feasible that both are due to the accumulation of toxic metabolite(s), and arene oxides may probably be considered as damaging derivatives of carbamazepine metabolism. Despite the lack of clear-cut underlying clinical and experimental findings in those patients in whom an inherited weakness of drug eliminating capacity is present, those conditions that may deteriorate glutathione balance, may increase the possibility of the emergence of toxic events during carbamazepine therapy. Finally, some recommendations for carbamazepine therapy are presented.

Protective Role of Melatonin and Taurine Against Carbamazepine-induced Toxicity in Freshly Isolated Rat Hepatocytes

“…We established cytoprotectiv estrategies concerning the hepatotoxicity associated with carbamazepine therapy. The toxicity was investigated in hepatocytes induced by phenobarbital (CYP450 inducer), because of the probability that the intermediate areneoxides formed in biotransformation might be the causes of the toxicity (Bavdekar et al;Kalapos, 2002;Madden et al, 1996;Shear & Spielberg, 1988). The results of our study showed that oxidative stress was involved in hepatotoxicity induced by carbamazepine and its metabolites.…”

Bioaccumulation and bioconcentration of carbamazepine and other pharmaceuticals in fish under field and controlled laboratory experiments. Evidences of carbamazepine metabolization by fish

“…The first pathway includes the formation of carbamazepine-10, 11-epoxide (CBZ-EP), the principal metabolite of CBZ with anticonvulsant properties, which is almost completely hydrolyzed to 10,11-dihydro-10,11-trans-dihydroxycarbamazepine (diOH-CBZ) before excretion. This pathway is mainly mediated by the cytochrome P450 (CYP) CYP3A4 isozyme, while a minor role is attributed to CYP2C8 (Kalapos, 2002). Another pathway is the hydroxylation of the six-membered aromatic ring, leading to the formation of 2-hydroxycarbamazepine (2-OH-CBZ), 3-OH-CBZ, 1-OH-CBZ, etc.…”

Human in Vitro Glutathionyl and Protein Adducts of Carbamazepine-10,11-Epoxide, a Stable and Pharmacologically Active Metabolite of Carbamazepine

“…The clinical use of CBZ, an anticonvulsant, has been associated with a variety of idiosyncratic adverse reactions, such as generalized reactions, hepatotoxicity, and hematological disorders (Hart and Easton, 1982;Shear et al, 1988;Kalapos, 2002). CBZ-induced adverse reactions have been reported in as many as 30 to 50% of all patients treated with this drug (Pellock, 1987;Durelli et al, 1989).…”

“…Although the mechanisms behind these adverse reactions are not clear, they are proposed to result from the formation of chemically reactive metabolites (Shear et al, 1988). An arene oxide intermediate has been postulated to be responsible for the idiosyncratic toxicity of CBZ (Pirmohamed et al, 1992;Lillibridge et al, 1996;Madden et al, 1996;Amore et al, 1997;Masubuchi et al, 2001;Kalapos, 2002). However, it has been difficult to achieve definitive proof of the arene oxide due to its high instability.…”