Received for publication September 20, 2007.
Revised November 6, 2007.
Accepted for publication November 12, 2007.

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

Abstract

Rodent tissue distribution and pharmacokinetic studies were performed on basic compounds Org A and Org B in support of CNS drug discovery programs. A consistent observation from these studies was that drug concentrations in plasma obtained by cardiac puncture after CO₂ euthanasia were markedly higher compared to other sampling methods (serial sampling, isofluorane anaesthesia or cervical dislocation). Further investigations demonstrated that CO₂ 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 CO₂ 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. CO₂ euthanasia prior to sampling, resulted in a 2-3 fold increase in AUC, decrease in CL and decrease in steady state volume of distribution compared to isofluorane anaesthesia. It is proposed that a decrease in the pH of blood relative to that of other tissues, as a consequence of CO₂ exposure, results in a redistribution of basic compounds out of the tissues, leading to higher concentrations in plasma.

Key words: blood-brain barrier, CNS pharmacokinetics, distribution, drug distribution, pharmacokinetics