Djerad A, Monier C, Houzé P, Borron S W, Lefauconnier J M, Baud F J
INSERM U26, Université Paris 7, Hôpital Fernand Widal, 200 rue du Faubourg Saint-Denis, 75010 Paris, France.
Toxicol Sci. 2001 Jun;61(2):273-82. doi: 10.1093/toxsci/61.2.273.
The aim of this study was to determine whether respiratory acidosis favors the cerebral distribution of cyanide, and conversely, if respiratory alkalosis limits its distribution. The pharmacokinetics of a nontoxic dose of cyanide were first studied in a group of 7 rats in order to determine the distribution phase. The pharmacokinetics were found to best fit a 3-compartment model with very rapid distribution (whole blood T(1/2)alpha = 21.6 +/- 3.3 s). Then the effects of the modulation of arterial pH on the distribution of a nontoxic dose of intravenously administered cyanide into the brains of rats were studied by means of the determination of the permeability-area product (PA). The modulation of arterial blood pH was performed by variation of arterial carbon dioxide tension (PaCO2) in 3 groups of 8 anesthetized mechanically ventilated rats. The mean arterial pH measured 20 min after the start of mechanical ventilation in the acidotic, physiologic, and alkalotic groups were 7.07 +/- 0.03, 7.41 +/- 0.01, and 7.58 +/- 0.01, respectively. The mean PAs in the acidotic, physiologic, and alkalotic groups, determined 30 s after the intravenous administration of cyanide, were 0.015 +/- 0.002, 0.011 +/- 0.001, and 0.008 +/- 0.001 s(-1), respectively (one-way ANOVA; p < 0.0087). At alkalotic pH the mean permeability-area product was 43% of that measured at acidotic pH. This effect of pH on the rapidity of cyanide distribution does not appear to be limited to specific areas of the brain. We conclude that modulation of arterial pH by altering PaCO2 may induce significant effects on the brain uptake of cyanide.
本研究的目的是确定呼吸性酸中毒是否有利于氰化物在脑内的分布，反之，呼吸性碱中毒是否会限制其分布。首先在一组7只大鼠中研究了无毒剂量氰化物的药代动力学，以确定其分布阶段。发现药代动力学最符合三室模型，分布非常迅速（全血T(1/2)α = 21.6 ± 3.3秒）。然后通过测定通透面积乘积（PA），研究了动脉pH调节对静脉注射无毒剂量氰化物在大鼠脑内分布的影响。通过改变3组每组8只机械通气麻醉大鼠的动脉二氧化碳分压（PaCO2）来调节动脉血pH。酸中毒组、生理组和碱中毒组在机械通气开始后20分钟测得的平均动脉pH分别为7.07 ± 0.03、7.41 ± 0.01和7.58 ± 0.01。在静脉注射氰化物后30秒测定的酸中毒组、生理组和碱中毒组的平均PA分别为0.015 ± 0.002、0.011 ± 0.001和0.008 ± 0.001 s(-1)（单因素方差分析；p < 0.0087）。在碱中毒pH条件下，平均通透面积乘积是酸中毒pH条件下测得值的43%。pH对氰化物分布速度的这种影响似乎并不局限于脑的特定区域。我们得出结论，通过改变PaCO2调节动脉pH可能会对脑摄取氰化物产生显著影响。
