Relationship between chemical structure and physicochemical properties of series of bulky organic cations and their hepatic uptake and biliary excretion rates

Hans Proost, J Roggeveld, J.MKH Wierda, D.K F Meijer

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Abstract

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.

Original languageEnglish
Pages (from-to)715-726
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume282
Issue number2
Publication statusPublished - Aug-1997

Keywords

  • NEUROMUSCULAR BLOCKING-AGENTS
  • STEROIDAL MUSCLE-RELAXANTS
  • PUTATIVE METABOLITES
  • PARAMETER-ESTIMATION
  • VECURONIUM BROMIDE
  • AMMONIUM-COMPOUNDS
  • LIVER LYSOSOMES
  • D-TUBOCURARINE
  • PHARMACOKINETICS
  • TRANSPORT

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