title: Metabolism of lamotrigine to a reactive arene oxide intermediate.
abstract: Lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine] is an antiepileptic drug associated with hypersensitivity reactions which are thought to be an immunological response to metabolically generated drug-protein adducts. The o-dichlorophenyl moiety is a potential site for bioactivation of the drug to an arene oxide. The metabolites of [(14)C]lamotrigine (78 micromol/kg, iv) in adult male Wistar rats were characterized with particular reference 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 bladder urine after 4 h. Bile contained [(14)C]lamotrigine (1.4 +/- 0.3%), a glutathione adduct of [(14)C]dihydrohydroxylamotrigine (1.8 +/- 0.3%), i.e., an adduct of an arene oxide, and the glutathione (1.5 +/- 0.7%), cysteinylglycine (1.9 +/- 0.5%), and N-acetylcysteine (0.4 +/- 0.2%) adducts of [(14)C]lamotrigine. Formation of the thioether metabolites was partially blocked by the cytochrome P450 inhibitor, ketoconazole. Urine contained [(14)C]lamotrigine (4.5 +/- 0.5%) and [(14)C]lamotrigine N-oxide (0.9 +/- 0.2%). The radiolabeled material in skin (15.6 +/- 1.4%) was almost entirely [(14)C]lamotrigine. Isolated rat hepatocytes achieved a low rate of turnover to the glutathione adduct and N-oxide. However, neither rat nor human liver microsomes catalyzed NADPH-dependent irreversible binding. Lamotrigine can be bioactivated to an arene oxide by rat hepatocytes in the absence of a major competing pathway such as N-glucuronidation. Inhibition of N-glucuronidation has been associated with an increased risk of skin reactions in patients.
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool L69 3BX, United Kingdom.
authors.forename: J L
authors.initials: JL
authors.lastname: Maggs
authors.forename: D J
authors.initials: DJ
authors.lastname: Naisbitt
authors.forename: J N
authors.initials: JN
authors.lastname: Tettey
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002250:Carbon Radioisotopes; D004852:Epoxy Compounds / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D000077213:Lamotrigine; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014227:Triazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine
chemical_list: D000927:Anticonvulsants; D002250:Carbon Radioisotopes; D004852:Epoxy Compounds; D014227:Triazines; D000077213:Lamotrigine