Hepatic uptake and biliary excretion of d-tubocurarine and trimethyltubocurarine in the rat in vivo and in isolated perfused rat livers

Abstract

The clearance from perfusion medium and the biliary excretion of d-tubocurarine (d-TC) and trimethyltubocurarine (tMeTC) was studied in isolated perfused rat livers. Despite the related structure, d-TC exhibited considerably higher lipophilicity and plasma protein binding than its trimethyl derivative. Significant differences in hepatic disposition of the two agents were found. The clearance constant of elimination from the perfusate for d-TC was 2.00 and 0.41 ml/min for tMeTC. Fifty-one percent of the administered d-TC was excreted in the bile during 2 hours of perfusion. For tMeTC this amounted to only 16%. Bile/plasma concentration ratios of d-TC were 10 times those of tMeTC. There was no evidence for biotransformation of the substances. The unequal biliary output cannot be explained by differences in subcellular distribution. After injection into rats in vivo, the major part of drug in the liver is confined to the particulate fractions. Subfractionation studies indicate binding to lysosomes. The hepatocyte cytosol concentrations of d-TC and tMeTC are in the same order and are lower than the concomitant plasma concentrations. Both bile/liver and liver/plasms concentration ratios were higher for d-TC. The results support the idea that the balance of hydrophilic and hydrophobic properties is an important factor determining hepatic transport of organic compounds.