The effect of hepatectomy and plasma cholinesterase inhibition on cocaine metabolism and cardiovascular responses in pigs

To determine the effects of total hepatectomy and inhibition of plasma cholinesterase activity on cocaine metabolism, we measured plasma concentrations of cocaine and its three major metabolites, benzoylecgonine, ecgonine methyl ester, and norcocaine, by high-performance liquid chromatography in three groups of male pigs. Pigs were anesthetized with sodium thiopental and lungs were ventilated with nitrous oxide in oxygen. A right carotid arterial cannula and an internal jugular venous catheter were then inserted for the administration of cocaine and for blood sampling. A Swan-Ganz catheter was inserted through the right internal jugular vein. Group 1 pigs underwent sham operation; group 2 and 3 pigs underwent hepatectomy and portocaval shunt. In addition, group 3 pigs were treated with tetraisopropyl pyrophosphoramide, a specific plasma cholinesterase inhibitor. After this preparation, pigs were given 4 mg/kg cocaine intravenously over 2 minutes. After cocaine injection, 4 ml blood was collected into heparinized test tubes containing 2.5% sodium fluoride for determination of cocaine and its metabolites at 2, 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, and 300 minutes. We also measured hemodynamic responses after cocaine administration, including heart rate and rhythm, cardiac output, and arterial blood pressure. Data were analyzed by analysis of variance. Blood levels of cocaine and its metabolites were significantly different among the three groups (p < 0.05 by analysis of variance). Our results show that total hepatectomy was associated with a marked slowing of cocaine metabolism, absence of norcocaine, and increased benzoylecgonine levels when compared with the baseline values in the control pigs. Hepatectomy and plasma cholinesterase inhibition together were associated with a marked decrease in ecgonine methyl ester levels in group 3 compared with group 1 (control pigs) and group 2 (anhepatic pigs). Our results also indicate that plasma cholinesterase inhibition has a protective effect against cardiovascular disturbances induced by cocaine administration in anhepatic animals.