Flanagan R J, Amin A, Seinen W
Medical Toxicology Unit, Guy's and St Thomas' Hospital Trust, Avonley Road, London SE14 5ER, UK.
Forensic Sci Int. 2003 Mar 12;132(1):9-17. doi: 10.1016/s0379-0738(02)00414-0.
Interpretation of the results of psychoactive or other drug measurements in post-mortem blood specimens may not be straightforward, in part because analyte concentrations in blood may change after death. There is also the issue of comparability of plasma (or serum) results to those obtained in whole blood. To investigate these problems with respect to clozapine, this drug (10mg/kg daily) was given orally to two pigs. Blood was collected 3h post-dose on day 7, the animals were sacrificed, and blood taken from central and peripheral veins for up to 48 h after death. Tissue samples were also collected immediately after death and at 48 h. Ante-mortem whole blood clozapine/N-desmethylclozapine (norclozapine) concentrations were 0.86/1.07 and 1.11/1.15 mg/l in pigs 1 and 2, respectively. Blood clozapine and norclozapine concentrations generally increased after death (central vein: clozapine up to 300%, norclozapine up to 460%; peripheral vein: clozapine up to 155%, norclozapine up to 185%). Initial blood and kidney clozapine and norclozapine concentrations were comparable in both animals, but were some two-fold higher in heart, liver and striated muscle in pig 2. In both animals, the heart and striated muscle clozapine and norclozapine concentrations had increased some two- to three-fold at 48 h, whilst the liver and kidney concentrations were essentially unchanged. The reason for the increase in heart and striated muscle concentrations at 48 h is unclear, but could be simple variation in sample site. The plasma:whole blood distribution of clozapine and norclozapine was studied in vitro. In human blood (one volunteer donor, haematocrit 0.50) the plots of plasma versus whole blood concentration were linear for both analytes across the range 0.1-1.5mg/l, although clozapine favoured plasma (plasma:whole blood ratio=1.12), whereas norclozapine favoured whole blood (ratio 0.68). In pig blood, the plots of plasma versus whole blood were non-linear in both cases, although clozapine favoured plasma to a greater extent than norclozapine. This may be due to lower plasma clozapine and norclozapine protein binding capacity in the pig as compared to man.
对死后血液样本中精神活性药物或其他药物检测结果的解读可能并非易事，部分原因是死后血液中的分析物浓度可能会发生变化。此外，血浆（或血清）结果与全血结果的可比性也存在问题。为了研究氯氮平的这些问题，给两只猪口服这种药物（每日10mg/kg）。在给药第7天，给药后3小时采集血液，处死动物，并在死后长达48小时从中心静脉和外周静脉采集血液。死后立即和48小时时也采集组织样本。猪1和猪2生前全血中氯氮平/N-去甲基氯氮平（去甲氯氮平）的浓度分别为0.86/1.07和1.11/1.15mg/l。死后血液中氯氮平和去甲氯氮平的浓度通常会升高（中心静脉：氯氮平最高升高300%，去甲氯氮平最高升高460%；外周静脉：氯氮平最高升高155%，去甲氯氮平最高升高185%）。两只动物最初血液和肾脏中氯氮平和去甲氯氮平的浓度相当，但猪2心脏、肝脏和横纹肌中的浓度约高出两倍。在两只动物中，48小时时心脏和横纹肌中氯氮平和去甲氯氮平的浓度增加了约两到三倍，而肝脏和肾脏中的浓度基本未变。48小时时心脏和横纹肌中浓度增加的原因尚不清楚，但可能是样本采集部位的简单差异。在体外研究了氯氮平和去甲氯氮平的血浆：全血分布情况。在人血（一名志愿者供体，血细胞比容0.50）中，两种分析物在0.1-1.5mg/l范围内血浆与全血浓度的关系图均为线性，尽管氯氮平更倾向于分布在血浆中（血浆：全血比率=1.12），而去甲氯氮平更倾向于分布在全血中（比率0.68）。在猪血中，两种情况下血浆与全血的关系图均为非线性，尽管氯氮平比去甲氯氮平更倾向于分布在血浆中。这可能是因为与人类相比，猪血浆中氯氮平和去甲氯氮平的蛋白结合能力较低。
