TY - JOUR T1 - Oxidative Metabolism of Bupivacaine into Pipecolylxylidine in Humans Is Mainly Catalyzed by CYP3A JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 383 LP - 385 VL - 28 IS - 4 AU - Manon Gantenbein AU - Laurence Attolini AU - Bernard Bruguerolle AU - Pierre-Henri Villard AU - Franck Puyoou AU - Alain Durand AU - Bruno Lacarelle AU - Jean Hardwigsen AU - Yves-Patrice Le-Treut Y1 - 2000/04/01 UR - http://dmd.aspetjournals.org/content/28/4/383.abstract N2 - Bupivacaine is used to provide prolonged anesthesia and postoperative analgesia. The human cytochrome P450 (CYP) involved in bupivacaine degradation into pipecolylxylidine (PPX), its major metabolite, has, to our knowledge, never been described. Microsome samples were prepared from six human livers and incubated in the presence of bupivacaine. The concentrations of PPX in the microsomal suspensions were assessed, and Km andVmax values were calculated. Bupivacaine incubations were then performed with specific CYP substrates and inhibitors. For each sample of hepatic microsomes, the correlation between the rate of PPX formation and the corresponding erythromycinN-demethylase activity was analyzed. Finally, an immunoinhibition study using an anti-rabbit CYP3A6 antibody and assays with cDNA-expressed human CYP were conducted. The apparentKm and Vmaxvalues of bupivacaine were, respectively, 125 μM and 4.78 nmol/min/mg of microsomal protein. The strongest inhibition of bupivacaine metabolism was obtained for troleandomycin (−95% at 50 μM), a specific CYP3A inhibitor. The correlation between PPX formation and erythromycin N-demethylase activity showed anR value of 0.99 whereas anti-rabbit CYP3A6 antibody inhibited the degradation of bupivacaine into PPX by 99%. Finally, CYP1A2 and CYP2E1 cDNA-expressed forms of human CYP did not allow PPX formation, CYP2C19 and CYP2D6 produced only small amounts whereas CYP3A4 most efficiently metabolized bupivacaine into PPX. These results demonstrated that bupivacaine degradation into PPX was mediated in humans by CYP3A. The American Society for Pharmacology and Experimental Therapeutics ER -