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The Potential Influence of CO₂, as an Agent for Euthanasia, on the Pharmacokinetics of Basic Compounds in Rodents

Department of Pharmacology, Organon Laboratories Ltd., Newhouse, Lanarkshire, United Kingdom

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 CO₂ euthanasia were markedly higher compared with those from other sampling methods (serial sampling, isoflurane anesthesia, 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 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 CO₂ exposure, results in a redistribution of basic compounds out of the tissues, leading to higher concentrations in plasma.