Possible bioactivation pathways of lamotrigine.
The anticonvulsant lamotrigine is associated with idiosyncratic drug reactions, especially skin rashes. Most idiosyncratic reactions are believed to be caused by reactive metabolites. Previous studies have found evidence that an arene oxide is formed in rats; however, when we incubated radiolabeled lamotrigine with rat liver microsomes virtually no covalent binding was detected, and the expected downstream phenolic metabolites are not observed in humans. Rare cases of agranulocytosis have been associated with lamotrigine therapy, and we found that lamotrigine is oxidized to two different N-chloro products by HOCl. The more reactive N-chloro metabolite forms an adduct with N-acetylhistidine, and covalent binding was observed when radiolabeled lamotrigine was incubated with myeloperoxidase/H(2)O(2)/Cl(-). Another lamotrigine metabolite is an N-oxide. If this N-oxide were sulfated, it might be sufficiently reactive to bind to protein. The synthetic N-sulfate reacted with N-acetylserine; however, no covalent binding was detected when the radiolabeled N-oxide was incubated with sulfotransferase. We also investigated the possibility that lamotrigine might be oxidized to a free radical by other peroxidases or oxidized by other enzymes such as prostaglandin H synthase or tyrosinase, but no evidence of oxidation was found, and lamotrigine did not cause any detectable increase in lipid peroxidation in vivo. In view of the virtual lack of covalent binding to hepatic microsomes and the lack of any other likely pathway leading to metabolic activation in the skin, it is possible that the parent drug rather than a reactive metabolite causes lamotrigine-induced skin rashes.
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Wei
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Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Uetrecht
Jack P
JP
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D003875:Drug Eruptions / Q000209:etiology; D005260:Female; D006801:Humans; D006868:Hydrolysis; D006997:Hypochlorous Acid / Q000737:chemistry; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013431:Sulfates / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014227:Triazines / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*
D000927:Anticonvulsants; D016877:Oxidants; D013431:Sulfates; D014227:Triazines; D006997:Hypochlorous Acid; D009195:Peroxidase; D000077213:Lamotrigine