Involvement of liver carboxylesterases in the in vitro metabolism of lidocaine
Involvement of liver carboxylesterases in the in vitro metabolism of lidocaine
复制标题
DOI：
10.1124/dmd.30.6.643
复制
发表时间：
2002-06-01
影响因子：
3.9
通讯作者：
Swedmark, S
中科院分区：
文献类型：
--
作者：
Alexson, SEH;Diczfalusy, M;Swedmark, S
利多卡因的临床应用已有半个多世纪，但其代谢机制尚未完全阐明。在本研究中，我们讨论了利多卡因代谢为2，6-二甲基苯胺的羟基化、脱乙基化和酯水解的参与。使用从雄性大鼠肝脏中分离的微粒体，我们发现利多卡因主要通过脱乙基代谢为N-（N-乙基甘氨酰）-2，6-二甲基苯胺，N-（N-乙基甘氨酰）-2，6-二甲基苯胺主要代谢为N-甘氨酰-2，6-二甲基苯胺，也通过脱乙基代谢。然而，在NADPH非依赖性反应中，2，6-二甲基苯胺可以由利多卡因和N-（N-乙基甘氨酰基）-2，6-二甲基苯胺形成，但不能由N-甘氨酰基-2，6-二甲基苯胺形成，这表明这些化合物中的酰胺键可以被酯酶直接水解。为了检验这一假设，我们将利多卡因、N-（N-乙基甘氨酰）-2，6-二甲基苯胺和N-甘氨酰-2，6-二甲基苯胺与纯化的肝羧酸酯酶一起孵育。大鼠肝微粒体羧酸酯酶ES-10（而非羧酸酯酶ES-4）将利多卡因和N-（N-乙基甘氨酰）2，6-二甲基苯胺水解为2，6-二甲基苯胺，确定该酯酶为利多卡因代谢中的候选酶。
Although lidocaine has been used clinically for more than half a century, the metabolism has still not been fully elucidated. In the present study we have addressed the involvement of hydroxylations, deethylations, and ester hydrolysis in the metabolism of lidocaine to 2,6-xylidine. Using microsomes isolated from male rat liver, we found that lidocaine is mainly metabolized by deethylation to N-(N-ethylglycyl)-2,6-xylidine, and N-(N-ethylglycyl)-2,6-xylidine is mainly metabolized to N-glycyl-2,6-xylidine, also by deethylation. However, 2,6-xylidine can be formed both from lidocaine and N-(N-ethylglycyl)-2,6-xylidine, but not from N-glycyl-2,6-xylidine, in an NADPH-independent reaction, suggesting that the amido bond in these compounds can be directly hydrolyzed by esterases. To test this hypothesis, we incubated lidocaine, N-(N-ethylglycyl)-2,6-xylidine, and N- glycyl-2,6-xylidine with purified liver carboxylesterases. Rat liver microsomal carboxylesterase ES-10, but not carboxylesterase ES-4, hydrolyzed lidocaine and N-(N-ethylglycyl) 2,6-xylidine to 2,6-xylidine, identifying this esterase as a candidate enzyme in the metabolism of lidocaine.