title: Effect of pretreatment with CBDP on the toxicokinetics of soman stereoisomers in rats and guinea pigs.
abstract: Pretreatment of rats and guinea pigs with the specific carboxylesterase inhibitor 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP) reduces the LD50 of the nerve agent C(+/-)P(+/-)-soman in these species to the same range as in primates. This suggests that such CBDP-pretreated animals can be used in investigations that are relevant for prophylaxis and therapy of intoxication with C(+/-)P(+/-)-soman in primates including humans. In order to test this hypothesis we have studied the toxicokinetics of the toxic C(+/-)P(-)-isomers of soman in artificially respirated and CBDP-pretreated rats and guinea pigs at intravenous doses corresponding to 6x LD50. A comparison of the areas under the curve (AUCs) of the blood levels of C(+/-)P(-)-soman in pretreated and non-pretreated animals at the same absolute dose shows extreme nonlinearity with dose, indicating that CBDP occupies highly reactive binding sites which are no longer available for sequestration of the soman isomers. The AUCs of C(+/-)P(-)-soman at equitoxic doses of 6x LD50 are reduced by pretreatment with CBDP from 1683 to 464 ng.min.ml-1 in rats and from 978 to 176 ng.min.ml-1 in guinea pigs, which is in the range of the AUC in non-pretreated marmosets at an equitoxic dose (419 ng.min.ml-1). The blood levels of the C(+/-)P(-)-isomers in marmosets and CBDP rats are rather similar during the first 7 min, but persist in CBDP rats for 2 h longer at toxicologically relevant levels than in marmosets.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: TNO Prins Maurits, Rijswijk, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Due
authors.forename: H C
authors.initials: HC
authors.lastname: Trap
authors.forename: H J
authors.initials: HJ
authors.lastname: Van Der Wiel
authors.forename: H P
authors.initials: HP
authors.lastname: Benschop
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000493:pharmacokinetics / Q000633:toxicity*; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D009943:Organophosphorus Compounds; C000516:2-(2-cresyl)-4H-1-3-2-benzodioxaphosphorin-2-oxide; D012999:Soman