Vol. 292, Issue 3, 861-869, March 2000

Structure-Pharmacokinetics Relationship of Series of Aminosteroidal Neuromuscular Blocking Agents in the Cat¹

Johannes H. Proost , J. Mark K. H. Wierda, Martin C. Houwertjes, Jan Roggeveld and Dirk K. F. Meijer

Groningen University Institute for Drug Exploration, University Centre for Pharmacy, Department of Pharmacokinetics and Drug Delivery, University of Groningen, Groningen (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.M.K.H.W., M.C.H., J.R.)

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 · min¹ · kg¹. 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.