The objective of the present study was to determine (1) the influence of
sarin poisoning (144 microg/kg s.c.) on the pharmacokinetics and brain distribution of the
adenosine A1 receptor partial agonist
2'-deoxy-N6-cyclopentyladenosine (
2'dCPA), and (2) the effect of
2'dCPA (20 mg/kg i.v.) on the central
acetylcholine (ACh) release and protection against
sarin toxicity. A five-compartment model successfully described the pharmacokinetic profile of
2'dCPA in blood and brain microdialysate. A covariate analysis revealed that the volume of distribution of
2'dCPA in blood was different in
sarin-poisoned rats, 177 +/- 7 versus 148 +/- 8 ml in control rats. However, the transport of
2'dCPA from blood to the brain was unaffected as reflected by the values of the intercompartmental transport clearances, 0.21 +/- 0.02 and 0.21 +/- 0.04 microl/min in control and
sarin-poisoned rats, respectively. Also the area-under-curve (AUC) ratios of brain microdialysate and blood were identical with values of 0.02 +/- 0.001 and 0.02 +/- 0.002, respectively, demonstrating the restricted transport of
2'dCPA into the brain in both treatment groups. Treatment of
sarin-poisoned rats by
2'dCPA did not adequately prevent the accumulation of ACh in the central nervous system.
2'dCPA delayed the emergence of concomitant symptoms compared to untreated rats, but eventually only 29% of the animals survived 24 h. In conclusion, the pharmacokinetic profile of
2'dCPA in blood was slightly changed by
sarin, but not the distribution of
2'dCPA into the brain. The therapeutic efficacy of
2'dCPA against
sarin was limited, presumably due to insufficient quantities of
2'dCPA reaching the brain.