Sinz M W, Remmel R P
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Drug Metab Dispos. 1991 Jan-Feb;19(1):149-53.
Lamotrigine (LTG) is a novel triazine anticonvulsant currently undergoing clinical trials. LTG N-glucuronide, the major human metabolite of LTG, was isolated from human urine by means of XAD-2 column chromatography and semi-preparative HPLC. The structure of the suspected lamotrigine 2-N-glucuronide was proven by mass spectroscopy and NMR spectroscopy, along with chemical and enzymatic hydrolysis studies. High resolution fast atom bombardment mass spectrometry and Electrospray tandem mass spectrometry of the glucuronide gave an M+ ion at 432.0 amu and a fragment ion at 256.0 (M - 176)+ amu. The proton NMR of the glucuronide indicated the presence of a glucuronic acid moiety. A downfield anomeric proton (5.35-5.60 ppm) implied direct attachment to the aromatic triazine ring. Carbon-13 NMR of the glucuronide revealed an upfield shift (delta = -7.0 ppm) of the C-3 carbon of the triazine ring compared to LTG, indicating attachment of the glucuronide to the N-2 position. Chemical degradation or rearrangement of the glucuronide occurs at neutral pH to produce an unknown product (RP-1), while at basic pH a different unknown product (RP-2) is formed. The glucuronide is unusually stable at acidic pH. Treatment of the glucuronide with beta-glucuronidase resulted in hydrolysis to LTG, and enzymatic hydrolysis was inhibited by saccharo-1,4-lactone.
拉莫三嗪（LTG）是一种新型的三嗪类抗惊厥药，目前正在进行临床试验。LTG的主要人体代谢产物拉莫三嗪N-葡萄糖醛酸苷，通过XAD - 2柱色谱法和半制备高效液相色谱法从人尿中分离出来。通过质谱、核磁共振光谱以及化学和酶促水解研究，证实了疑似拉莫三嗪2 - N - 葡萄糖醛酸苷的结构。葡萄糖醛酸苷的高分辨率快原子轰击质谱和电喷雾串联质谱给出了质荷比为432.0 amu的M +离子和质荷比为256.0（M - 176）+ amu的碎片离子。葡萄糖醛酸苷的质子核磁共振表明存在葡萄糖醛酸部分。一个低场端基异构质子（5.35 - 5.60 ppm）意味着直接连接到芳族三嗪环上。与LTG相比，葡萄糖醛酸苷的碳-13核磁共振显示三嗪环的C - 3碳有一个高场位移（δ = -7.0 ppm），表明葡萄糖醛酸苷连接到N - 2位。葡萄糖醛酸苷在中性pH下会发生化学降解或重排，生成一种未知产物（RP - 1），而在碱性pH下会形成另一种不同的未知产物（RP - 2）。葡萄糖醛酸苷在酸性pH下异常稳定。用β-葡萄糖醛酸酶处理葡萄糖醛酸苷会水解生成LTG，并且糖-1,4-内酯会抑制酶促水解。
