Lu Wei, Uetrecht Jack P
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Drug Metab Dispos. 2007 Jul;35(7):1050-6. doi: 10.1124/dmd.107.015271. Epub 2007 Apr 4.
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.
抗惊厥药物拉莫三嗪与特异质性药物反应有关，尤其是皮疹。大多数特异质性反应被认为是由反应性代谢产物引起的。先前的研究已发现大鼠体内会形成一种芳烃氧化物的证据；然而，当我们将放射性标记的拉莫三嗪与大鼠肝微粒体一起孵育时，几乎未检测到共价结合，且在人体内未观察到预期的下游酚类代谢产物。粒细胞缺乏症的罕见病例与拉莫三嗪治疗有关，我们发现拉莫三嗪被次氯酸氧化为两种不同的N -氯产物。反应性更强的N -氯代谢产物与N -乙酰组氨酸形成加合物，当放射性标记的拉莫三嗪与髓过氧化物酶/H₂O₂/Cl⁻一起孵育时可观察到共价结合。拉莫三嗪的另一种代谢产物是N -氧化物。如果这种N -氧化物被硫酸化，它可能具有足够的反应性与蛋白质结合。合成的N -硫酸盐与N -乙酰丝氨酸反应；然而，当放射性标记的N -氧化物与磺基转移酶一起孵育时未检测到共价结合。我们还研究了拉莫三嗪可能被其他过氧化物酶氧化为自由基或被其他酶如前列腺素H合酶或酪氨酸酶氧化的可能性，但未发现氧化的证据，且拉莫三嗪在体内未引起任何可检测到的脂质过氧化增加。鉴于与肝微粒体几乎不存在共价结合以及缺乏任何其他可能导致皮肤代谢活化的途径，有可能是母体药物而非反应性代谢产物导致拉莫三嗪引起的皮疹。
