Oda Y, Furuichi K, Tanaka K, Hiroi T, Imaoka S, Asada A, Fujimori M, Funae Y
Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Japan.
Anesthesiology. 1995 Jan;82(1):214-20. doi: 10.1097/00000542-199501000-00026.
Ropivacaine is a local anesthetic with a long duration of action. Although it is less toxic than bupivacaine, local anesthetic toxicity is possible when the plasma concentration is increased. Because ropivacaine is an amide-type local anesthetic, it is metabolized by cytochrome P450 (P450) in the liver, and its elimination and plasma concentration can be dependent on the level of P450. The purpose of this investigation was to elucidate the metabolism of ropivacaine by human hepatic P450.
The metabolism of ropivacaine was compared using recombinant human and purified rat hepatic P450 isozymes. An inhibition study using antibodies against rat P450 was performed using hepatic microsomes from human and rat to identify which P450s are involved in ropivacaine metabolism.
Ropivacaine was metabolized to 2',6'-pipecoloxylidide (PPX), 3'-hydroxyropivacaine (3'-OH Rop), and 4'-hydroxyropivacaine (4'-OH Rop) by hepatic microsomes from human and rat. PPX was a major metabolite of both human and rat hepatic microsomes. In a reconstituted system with rat P450. PPX was produced by CYP2C11 and 3A2, 4'-OH Rop by CYP1A2, and 3'-OH Rop by CYP1A2 and 2D1. Formation of PPX in rat hepatic microsomes was inhibited by anti CYP3A2, but not by CYP2C11 antibody, and formation of 3'-OH Rop was inhibited by CYP1A2 and 2D1 antibodies. Anti CYP3A2 and 1A2 antibodies inhibited the formation of PPX and 3'-OH Rop in human hepatic microsomes, respectively. Recombinant human P450s expressed in lymphoblast cells were used for further study. CYP3A4 and 1A2 formed the most PPX and 3'-OH Rop, respectively. Ropivacaine N-dealkylation and 3'-hydroxylation activities correlated well with the level of CYP3A4 and 1A2 in human hepatic microsomes, respectively.
Ropivacaine was metabolized to PPX, 3'-OH Rop, and 4'-OH Rop by hepatic P450. PPX was a major metabolite in human hepatic microsomes. CYP3A4 was involved in producing PPX. CYP1A2 was involved in the formation of 3'-OH Rop in human hepatic microsomes.
罗哌卡因是一种作用时间长的局部麻醉药。尽管它的毒性比布比卡因小，但当血浆浓度升高时仍有可能发生局部麻醉药中毒。由于罗哌卡因是酰胺类局部麻醉药，它在肝脏中由细胞色素P450（P450）代谢，其消除和血浆浓度可能取决于P450的水平。本研究的目的是阐明人肝P450对罗哌卡因的代谢情况。
使用重组人肝P450同工酶和纯化的大鼠肝P450同工酶比较罗哌卡因的代谢情况。用人和大鼠的肝微粒体进行抗大鼠P450抗体的抑制研究，以确定哪些P450参与罗哌卡因的代谢。
人和大鼠的肝微粒体将罗哌卡因代谢为2',6'-哌啶甲酰苯胺（PPX）、3'-羟基罗哌卡因（3'-OH Rop）和4'-羟基罗哌卡因（4'-OH Rop）。PPX是人和大鼠肝微粒体的主要代谢产物。在含有大鼠P450的重组系统中，PPX由CYP2C11和3A2产生，4'-OH Rop由CYP1A2产生，3'-OH Rop由CYP1A2和2D1产生。大鼠肝微粒体中PPX的形成受到抗CYP3A2抗体的抑制，但不受CYP2C11抗体的抑制，3'-OH Rop的形成受到CYP1A2和2D1抗体的抑制。抗CYP3A2和1A2抗体分别抑制人肝微粒体中PPX和3'-OH Rop的形成。在淋巴母细胞中表达的重组人P450用于进一步研究。CYP3A4和1A2分别形成最多的PPX和3'-OH Rop。罗哌卡因N-脱烷基化和3'-羟基化活性分别与人肝微粒体中CYP3A4和1A2的水平密切相关。
肝P450将罗哌卡因代谢为PPX、3'-OH Rop和4'-OH Rop。PPX是人肝微粒体中的主要代谢产物。CYP3A4参与PPX的产生。CYP1A2参与人肝微粒体中3'-OH Rop的形成。
