HEPATIC UPTAKE AND BILIARY-EXCRETION OF D-TUBOCURARINE AND TRIMETHYLTUBOCURARINE IN RAT INVIVO AND IN ISOLATED PERFUSED RAT LIVERS

  • 1 January 1976
    • journal article
    • research article
    • Vol. 198  (1) , 229-239
Abstract
Despite the related structure, d-tubocurarine[d-TC] exhibited considerably higher lipophilicity and plasma protein binding than its trimethyl derivative. Significant differences in hepatic disposition of the 2 agents were found. The clearance constant of elimination from the perfusate for d-TC was 2.00 and 0.41 ml/min for trimethyltubocurarine [tMeTC]. Of the administered d-TC 51% was excreted in the bile during 2 h 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/plasma concentration ratios were higher for d-TC. The balance of hydrophilic and hydrophobic properties is an important factor determining hepatic transport of organic compounds.