Epoxides

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Epoxide metabolites can be generated from a variety of aromatic systems. Anticonvulsants are a class of drug whose side-effects, such as hepatic necrosis and aplastic anaemia, are thought to be mediated by chemically reactive epoxide metabolites formed by cytochrome P450 oxidation. For instance phenytoin (Figure 8.6) toxicity is correlated with oxidation and the inhibition of epoxide hydrolase [8].

Carbamazepine exerts its anticonvulsant activity through its own action on voltage sensitive sodium channels and those of its relatively stable 10-11-epoxide. The compound shows a number of potential toxicities including skin rash, hepatic necrosis and teratogenicity. It is possible the 10-11-epoxide is the causative agent, but struc-

Fig. 8.6 Structure of pheny-toin, a drug believed to assert its toxicity through reactive epoxide metabolites.

tural studies [9] suggest other epoxide metabolites of the aromatic ring may be responsible in part. Oxcarbazepine (Figure 8.7) is a related drug that cannot form the 10-11-epoxide and owes part of its activity to its hydroxyl metabolite. Oxcarbazepine is much less teratogenic in animal models and shows a lower preponderance of skin rash [8,10].

Fig. 8.7 Structures of carbamezepine (A), its 10-11-epoxide metabolite (B), and oxcarbazepine (C) and its hydroxyl metabolite (D).

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