Effect of hypothermia on the hepatic uptake and biliary excretion of vecuronium in the isolated perfused rat liver.

Abstract

Hypothermia prolongs the time course of action of nondepolarizing muscle relaxants. It is not known whether this prolongation is caused by a reduced rate of extrahepatic distribution or elimination, liver uptake, metabolic clearance, or biliary excretion. Therefore, the authors studied the effects of hypothermia on the net hepatic uptake, metabolism, and biliary excretion of vecuronium in isolated perfused rat liver. Livers of Wistar rats were perfused with Krebs Ringer solution (1% albumin, 3.3% carbon dioxide in oxygen, pH 7.36-7.42, 38 degrees C). Each perfusion experiment (recirculatory perfusion system) was divided into three phases. In phase 1, a bolus dose of vecuronium (950 microg) was followed by a continuous infusion of vecuronium (63 microg/min) throughout the perfusion experiment. In phase 2, the temperature was reduced to 28 degrees C. In phase 3, temperature was restored. In controls, the temperature was kept constant throughout the perfusion. Concentrations of vecuronium and its metabolites were measured in perfusion medium, bile, and liver homogenate. Parameters of a multicompartmental liver model were fitted to the concentration patterns in perfusion medium and in bile. Hypothermia increased vecuronium concentrations in the perfusion medium from 4.0 microg/ml (range, 2.5-6.6) to 15.6 microg/ml (11.5-18.4 microg/ml; P = 0.018). Hypothermia reduced the biliary excretion rate of 3-desacetyl vecuronium from 18% (range, 6-37%) to 16% (range, 4-19%) of that of vecuronium (P = 0.018). Pharmacokinetic analysis confirmed that hypothermia reduced the rate constants of hepatic uptake and metabolism from 0.219 to 0.053 and from 0.059 to 0.030, respectively. Hypothermia significantly and reversibly reduced the net hepatic uptake of vecuronium. Hypothermia reduced the metabolism of vecuronium and the biliary excretion rate of 3-desacetyl vecuronium.