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Vol. 282, Issue 2, 715-726, 1997

Relationship between Chemical Structure and Physicochemical Properties of Series of Bulky Organic Cations and Their Hepatic Uptake and Biliary Excretion Rates1

Johannes H. Proost2 3 , Jan Roggeveld3 , J. Mark K. H. Wierda3 and Dirk K. F. Meijer2

Groningen Institute for Drug Studies (GIDS),4 University Centre for Pharmacy, Department of Pharmacokinetics and Drug Delivery, University of Groningen, Groningen, The Netherlands (J.H.P., J.R., D.K.F.M.); and Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Hospital, Department of Anesthesiology, Groningen, The Netherlands (J.H.P., J.R., J.M.K.H.W.)

To obtain more insight in the relationship between physicochemical properties of cationic drugs and their hepatobiliary transport rate, a series of 12 aminosteroidal neuromuscular blocking agents (NMBAs), supplemented with data of four related NMBAs from the literature, were investigated in the isolated perfused rat liver. A significant correlation was found between plasma protein binding and the partition coefficient octanol/Krebs (log P), confirming results from the literature with other organic cations. Evidence was found for a saturable hepatic uptake of several NMBAs, indicating that carrier-mediated uptake processes are involved. Hepatic uptake rate was closely related to the lipophilicity of the compounds; the initial extraction ratio, the apparent clearance and the intrinsic clearance were significantly correlated to log P. We did not find a significant correlation between biliary clearance and lipophilicity in the current series of compounds. Pharmacokinetics analysis of perfusate disappearance and biliary excretion data revealed that a considerable fraction of the dose of these bulky organic cations is stored in the liver and seems to not be directly available for biliary excretion. This finding is in line with earlier observations showing a pronounced accumulation of this type of compounds in mitochondria and lysosomes.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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