PT - JOURNAL ARTICLE AU - Johannes H. Proost AU - J. Mark K. H. Wierda AU - Martin C. Houwertjes AU - Jan Roggeveld AU - Dirk K. F. Meijer TI - Structure-Pharmacokinetics Relationship of Series of Aminosteroidal Neuromuscular Blocking Agents in the Cat DP - 2000 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 861--869 VI - 292 IP - 3 4099 - http://jpet.aspetjournals.org/content/292/3/861.short 4100 - http://jpet.aspetjournals.org/content/292/3/861.full SO - J Pharmacol Exp Ther2000 Mar 01; 292 AB - To obtain more insight in the relationship between physicochemical properties of neuromuscular blocking agents (NMBAs) and their pharmacokinetic characteristics, a series of 12 aminosteroidal NMBAs, supplemented with data on five related NMBAs from the literature, was investigated in anaesthetized cats. After i.v. bolus injection, plasma concentration decreased very rapidly, showing a biphasic pattern, with half-lives ranging from 0.4 to 1.4 min, and from 3 to 10 min, respectively. Clearance was in the range from 24 to 58 ml · min−1 · kg−1. Compounds containing an acetyl-ester group at position 3 were partly metabolized to the 3-OH derivative. The urinary excretion of the parent drug and metabolites amounted to <10% for each of the compounds. The parent drugs were excreted in large amounts into bile, along with smaller amounts of 3-OH derivatives. The terminal half-life of the urinary and biliary excretion rate were markedly longer than the apparent terminal half-life in plasma, ranging from 11 to 40 min, and from 119 to 489 min in urine and bile, respectively. Lipophilicity of the NMBAs, expressed as the partition coefficient octanol/Krebs (log P), was found to be correlated positively with unbound plasma clearance and unbound initial plasma clearance, and negatively with plasma half-life, volume of distribution at steady state, and mean residence time. The increase of the unbound plasma clearance with increasing lipophilicity is counteracted by the concurrent increase in plasma protein binding. The American Society for Pharmacology and Experimental Therapeutics