Ekström G, Gunnarsson U B
Department of Drug Metabolism, Astra Pain Control AB, Sweden.
Drug Metab Dispos. 1996 Sep;24(9):955-61.
Ropivacaine is a new amide-type local anesthetic agent. Unlike bupivacaine and mepivacaine, two structurally similar local anesthetic compounds, ropivacaine is exclusively the S-(-)-enantiomer. Ropivacaine is predominantly eliminated by extensive metabolism in the liver, with only 1% of the dose being excreted unchanged in the urine of humans. Four of the metabolites formed in human liver microsomes were identified as 3-OH-ropivacaine, 4-OH-ropivacaine, 2-OH-methyl-ropivacaine, and 2',6'-pipecoloxylidide (PPX). The enzymes involved in the human metabolism of ropivacaine have not been identified. To ascertain which forms of cytochrome P450 are involved, ropivacaine was incubated with human microsomes from 10 different livers having different cytochrome P450 activities. A strong correlation was found between the formation of 3-OH-ropivacaine and CYP1A (r = 0.87-0.89) and between the formation of 4-OH-ropivacaine, 2-OH-ropivacaine, and PPX and CYP3A (r = 0.97-1). Incubation of ropivacaine and human liver microsomes in the presence of alpha-naphthoflavone or furafylline, inhibitors of CYP1A, decreased the formation of 3-OH-ropivacaine by about 85%, without affecting the formation of the other metabolites. The formation of 4-OH-ropivacaine, 2-OH-methyl-ropivacaine, and PPX was markedly inhibited in the presence of troleandomycin, an inhibitor of CYP3A. Microsomes from cells expressing CYP1A2 formed 3-OH-ropivacaine, whereas 4-OH-ropivacaine, 2-OH-methyl-ropivacaine, and PPX were formed in microsomes from cells expressing CYP3A4. Inhibitors of CYP2C (sulfaphenazole), CYP2D6 (quinidine), and 2E1 (diethyldithiocarbamate) did not inhibit the formation of any metabolite from ropivacaine. In conclusion, CYP1A catalyzes the formation of 3-OH-ropivacaine, the main metabolite formed in vivo, whereas the formation of 4-OH-ropivacaine, 2-OH-methyl-ropivacaine, and PPX was catalyzed by CYP3A.
罗哌卡因是一种新型酰胺类局部麻醉药。与布比卡因和甲哌卡因这两种结构相似的局部麻醉化合物不同，罗哌卡因仅为S-(-)-对映体。罗哌卡因主要通过肝脏中的广泛代谢而消除，在人体尿液中仅有1%的剂量以原形排出。在人肝微粒体中形成的四种代谢产物被鉴定为3-羟基罗哌卡因、4-羟基罗哌卡因、2-羟基甲基罗哌卡因和2',6'-哌啶甲酰苯胺（PPX）。参与罗哌卡因人体代谢的酶尚未确定。为了确定涉及哪些形式的细胞色素P450，将罗哌卡因与来自10个具有不同细胞色素P450活性的不同肝脏的人微粒体一起孵育。发现3-羟基罗哌卡因的形成与CYP1A之间存在强相关性（r = 0.87 - 0.89），4-羟基罗哌卡因、2-羟基罗哌卡因和PPX的形成与CYP3A之间存在强相关性（r = 0.97 - 1）。在CYP1A抑制剂α-萘黄酮或呋拉茶碱存在的情况下，罗哌卡因与人肝微粒体的孵育使3-羟基罗哌卡因的形成减少了约85%，而不影响其他代谢产物的形成。在CYP3A抑制剂三乙酰竹桃霉素存在的情况下，4-羟基罗哌卡因、2-羟基甲基罗哌卡因和PPX的形成受到显著抑制。表达CYP1A2的细胞的微粒体形成3-羟基罗哌卡因，而表达CYP3A4的细胞的微粒体形成4-羟基罗哌卡因、2-羟基甲基罗哌卡因和PPX。CYP2C（磺胺苯吡唑）、CYP2D6（奎尼丁）和2E1（二乙基二硫代氨基甲酸盐）的抑制剂均未抑制罗哌卡因任何代谢产物的形成。总之，CYP1A催化体内主要代谢产物3-羟基罗哌卡因的形成，而4-羟基罗哌卡因、2-羟基甲基罗哌卡因和PPX的形成则由CYP3A催化。
