Alexson Stefan E H, Diczfalusy Margareta, Halldin Magnus, Swedmark Stellan
Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Drug Metab Dispos. 2002 Jun;30(6):643-7. doi: 10.1124/dmd.30.6.643.
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.
尽管利多卡因已在临床上使用了半个多世纪，但其代谢过程仍未完全阐明。在本研究中，我们探讨了羟基化、脱乙基化和酯水解在利多卡因代谢为2,6-二甲基苯胺过程中的作用。使用从雄性大鼠肝脏分离的微粒体，我们发现利多卡因主要通过脱乙基化代谢为N-（N-乙基甘氨酰）-2,6-二甲基苯胺，而N-（N-乙基甘氨酰）-2,6-二甲基苯胺也主要通过脱乙基化代谢为N-甘氨酰-2,6-二甲基苯胺。然而，2,6-二甲基苯胺可以由利多卡因和N-（N-乙基甘氨酰）-2,6-二甲基苯胺形成，但不能由N-甘氨酰-2,6-二甲基苯胺在不依赖NADPH的反应中形成，这表明这些化合物中的酰胺键可以被酯酶直接水解。为了验证这一假设，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脏羧酸酯酶一起孵育。大鼠肝脏微粒体羧酸酯酶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，确定该酯酶是利多卡因代谢中的候选酶。
