The potential influence of CO2, as an agent for euthanasia, on the pharmacokinetics of basic compounds in rodents
The potential influence of CO2, as an agent for euthanasia, on the pharmacokinetics of basic compounds in rodents
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DOI：
10.1124/dmd.107.018879
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发表时间：
2008-02-01
影响因子：
3.9
通讯作者：
Martin, Iain J.
中科院分区：
文献类型：
--
作者：
Angus, Derek W.;Baker, James A.;Martin, Iain J.
啮齿动物组织分布和药代动力学研究进行了基础化合物的CRAA和B，以支持中枢神经系统药物发现计划。这些研究的一致观察结果是，CO2安乐死后通过心脏穿刺获得的血浆药物浓度明显高于其他采样方法（连续采样、异氟烷麻醉或颈椎脱位）。进一步研究表明，CO2安乐死导致大鼠和小鼠血液pH值降低，而其他采样方法未观察到这一点。CO2安乐死的使用导致脑/血浆中β B的比例降低，主要是由于血浆浓度增加。基本药物雷洛昔芬在大鼠体内的药代动力学也受采样技术的影响。与异氟烷麻醉相比，采样前CO2安乐死导致药物浓度-时间曲线下面积增加2- 3倍，血浆清除率降低，稳态分布容积降低。有人提出，由于CO2暴露，血液pH值相对于其他组织的pH值降低，导致碱性化合物从组织中重新分布，导致血浆中浓度升高。
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.