title: Characterization of the pharmacokinetics, brain distribution, and therapeutic efficacy of the adenosine A1 receptor partial agonist 2'-deoxy-N6-cyclopentyladenosine in sarin-poisoned rats.
abstract: 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.
authors.affiliation: Research Group Medical Countermeasures, TNO Prins Maurits Laboratory, Lange Kleiweg 137, PO Box 45, 2280 AA Rijswijk, The Netherlands.
authors.forename: Tjerk J H
authors.initials: TJ
authors.lastname: Bueters
authors.forename: Ad P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: Herman P M
authors.initials: HP
authors.lastname: van Helden
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000506:poisoning*; D003839:Deoxyadenosines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis; D009206:Myocardium / Q000378:metabolism; D011041:Poisoning / Q000188:drug therapy; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017208:Rats, Wistar; D012524:Sarin / Q000506:poisoning*
chemical_list: C495036:2'-deoxyribose-N6-cyclopentyladenosine; D002619:Chemical Warfare Agents; D003839:Deoxyadenosines; D058906:Purinergic P1 Receptor Agonists; D012524:Sarin; D000109:Acetylcholine