CIGARETTE-SMOKE INCREASES BUPIVACAINE METABOLISM IN RATS

This study was designed to document possible changes in bupivacaine kinetics in rats after exposure to cigarette smoke. Rats (n = 15) were exposed to cigarette smoke (Borgwaldt type Hamburg II)for ten minutes per day during four days (C) or eight days (B); controls (A) were used simultaneously without exposure to cigarette smoke. After bupivacaine 20 mg.kg(-1) ip at day 4 (C) or day 8 (B), blood was sampled (0.5 ml of blood collected by puncture at the retro-orbital sinus 0.25, 0.5, 1, 2, 4, 6 and 8 hours after administration) and bupivacaine and its main metabolite i.e., desbutylbupivacaine (PPX) were determined by gas liquid chromatography. The sensitivity of the method was 15 ng.ml(-1) and the reproductibility was <6%. Serum bupivacaine concentrations were plotted against time and the pharmacokinetic variables were determined assuming a two compartment open model: Cmax, Tmax were derived directly from individual data. The beta phase elimination half-lives (T(1/2)beta), the area under the serum concentration curve (AUC(0)(infinity)), the total plasma clearance (CI) and the total volume of distribution (Vd) were calculated. These variables were assessed according to non-linear fitting method. Cigarette smoking exposure did not change the pharmacokinetic variables of bupivacaine. However the pharmacokinetic parameters of PPX, Cmax (0.175 +/- 0.007 mu g.ml(-1), 0.119 +/- 0.014 mu g.ml(-1) and 0.312 +/- 0.023 mu g.ml(-1), for groups A, B and C, respectively), AUC (0.170 +/- 0.006 mu g.ml(-1).hr(-1), 0.104 +/- 0.013 mu g.ml(-1.)hr(-1) and 0.433 +/- 0.017 mu g.ml(-1.)hr(-1) for groups A, B and C, respectively) and the ratio AUC PPX/ AUC bupivacaine (0.306 +/- 0.042, 0.153 +/- 0.021 and 0.660 +/- 0.054 for groups A, B and C, respectively were higher (P < 0.0001) for group C. These results indicate an enzymatic induction after only short exposure to cigarette smoking and justify further studies to document possible variations of the metabolism of bupivacaine induced by exposure to cigarette smoke in humans.