The potential influence of CO2, as an agent for euthanasia, on the pharmacokinetics of basic compounds in rodents.

Rodent tissue distribution and pharmacokinetic studies were performed on basic compounds Org A and Org B in support of central nervous system drug discovery programs. A consistent observation from these studies was that drug concentrations in plasma obtained by cardiac puncture after CO(2) euthanasia were markedly higher compared with those from other sampling methods (serial sampling, isoflurane anesthesia, or cervical dislocation). Further investigations demonstrated that CO(2) euthanasia led to a reduction in blood pH in both rats and mice, which was not observed with the other sampling methods. The use of CO(2) euthanasia resulted in a decrease in the brain/plasma ratio of Org B, largely as a result of increased plasma concentrations. The pharmacokinetics of a basic drug, raloxifene, in rat were also influenced by sampling technique. CO(2) euthanasia before sampling, resulted in a 2- to 3-fold increase in the area under the drug concentration-time curve, a decrease in plasma clearance, and a decrease in the steady-state volume of distribution compared with isoflurane anesthesia. It is proposed that a decrease in the pH of blood relative to that of other tissues, as a consequence of CO(2) exposure, results in a redistribution of basic compounds out of the tissues, leading to higher concentrations in plasma.

Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969.

BACKGROUND: The purpose of this study was to determine the changes in the plasma concentration of rocuronium and the reversal of its neuromuscular blockade after the intravenous infusion of Org 25969, the novel neuromuscular block-reversal agent, in anesthetized guinea pigs. METHODS: Rocuronium was infused for 1 h at a rate of 12-19 nmol.kg-1.min-1 to produce a steady-state 90% neuromuscular block. After 30 min, a concomitant infusion of either the reversal agent Org 25969 at a rate of 50 nmol.kg-1.min-1 or an infusion of an equivalent volume of saline was started. The time course of plasma concentrations of rocuronium was determined by use of liquid chromatography-mass spectrometry/mass spectrometry. RESULTS: In both treatment groups, a steady-state plasma concentration of rocuronium was obtained after 30 min. In the saline-treated group, the plasma concentration of rocuronium and depth of block remained constant. In the Org 25969 group, neuromuscular block was reversed while the rocuronium infusion was ongoing. Simultaneously, an increase in the total plasma concentration of rocuronium (free and complexed) was observed, even though the infusion rate of rocuronium was not changed. Compared with the saline-treated group, a small increase in the postmortem bladder concentration of rocuronium was detected. CONCLUSIONS: The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).

Anionic cyclophanes as potential reversal agents of muscle relaxants by chemical chelation.

A series of carboxyl-containing cyclophanes have been designed and synthesised as chemical chelators (or host molecules) of cationic muscle relaxant drugs (or guest molecules). Three of these cyclophane derivatives, 1-3, have been shown by NMR to form 1:1 complexes with the muscle relaxants pancuronium, and gallamine, in D(2)O, with association constants up to 10(4) M(-1). When tested in an in vitro chick biventer muscle preparation, the cyclophanes reversed the neuromuscular block induced by pancuronium and gallamine, with having the most effective reversal against pancuronium (EC(50) 40 microM.