Metabolism of lamotrigine to a reactive arene oxide intermediate

Lamotrigine [3,5-diamino-6-(2, 3-dichlorophenyl)-1,2,4-triazine] is an anti epileptic drug associated with hypersensitivity reactions which are thought to be an immunological response to metabolically generated drug-protein ad ducts. The o-dichlorophenyl moiety is a potential site for bioactivation of the drug to an arene oxide. The metabolites of [C-14]lamotrigine (78 mu mo l/kg, iv) in adult male Wistar rats were characterized with particular refe rence to thioether derivatives of an epoxide intermediate. Biliary recovery of radioactivity from anesthetized and cannulated animals was 7.3 +/- 3.0% (mean +/- SD, n = 4) of the dose over 4 h; 5.5 +/- 0.5% was recovered in b ladder urine after 4 h. Bile contained [C-14]lamotrigine (1.4 +/- 0.3%), a glutathione adduct of [C-14]dihydrohydroxylamotrigine (1.8 +/- 0.3%), i.e., an adduct of an arene oxide, and the glutathione (1.5 +/- 0.7%), cysteinyl glycine (1.9 +/- 0.5%), and N-acetylcysteine (0.4 +/- 0.2%) adducts of [C-1 4]lamotrigine. Formation of the thioether metabolites was partially blocked by the cytochrome P450 inhibitor, ketoconazole. Urine contained [C-14]lamo trigine (4.5 +/- 0.5%) and [C-14]lamotrigine N-oxide (0.9 +/- 0.2%). The ra diolabeled material in skin (15.6 +/- 1.4%) was almost entirely [C-14]lamot rigine. Isolated rat hepatocytes achieved a low rate of turnover to the glu tathione adduct and N-oxide. However, neither rat nor human liver microsome s catalyzed NADPH-dependent irreversible binding. Lamotrigine can be bioact ivated to an arene oxide by rat hepatocytes in the absence of a major compe ting pathway such as N-glucuronidation. Inhibition of N-glucuronidation has been associated with an increased risk of skin reactions in patients.