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Toxicological Sciences 61, 273-282 (2001)
Copyright © 2001 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Effects of Respiratory Acidosis and Alkalosis on the Distribution of Cyanide into the Rat Brain

Amina Djerad*, Claire Monier*, Pascal Houzé{dagger}, Stephen W. Borron*,{ddagger}, Jeanne-Marie Lefauconnier* and Frédéric J. Baud*,1

* INSERM U26, Université Paris 7, Hôpital Fernand Widal, 200 rue du Faubourg Saint-Denis, 75010 Paris, France; {dagger} Laboratoire de Biochimie A, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; and {ddagger} Department of Emergency Medicine, George Washington University Hospital, 901 23rd Street NW, Washington, DC 20037

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 T1/2{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.

Key Words: cyanide; pharmacokinetics; respiratory acidosis; respiratory alkalosis; brain.


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