Effects of pretreatment with 8018 on the toxicokinetics of soman in rabbits and distribution in mice.

The effects of 8018 [3-(2'-phenyl-2'-cyclopentyl-2'-hydroxyl-ethoxy)quinuclidine] on the elimination of soman in rabbits blood and distribution in mice brain and diaphragm were investigated using the chirasil capillary gas chromatographic analysis method. In all experiments, the concentration of P(+)soman was below the detection limit (<0.1 ng x mL(-1)). 8018 (1 mg x kg(-1), im, 10 min pre-treated) could significantly reduce the concentration of P(-)soman in rabbit blood from 53.6 +/- 13.3 to 26.2 +/- 9.70 ng x mL(-1) blood as compared to soman-treated control animal at 15 s following soman injection (43.2 microg x kg(-1), iv). Toxicokinetic parameters showed 8018 could increase clearance (CL((S))) from 20.8 +/- 1.54 to 38.2 +/- 15.3 mLx kg(-1) x s(-1) and reduce AUC of P(-)soman from 2.08 +/- 0.151 to 1.30 +/- 0.564 mg x s x L(-1). 8018 could reduce the concentration P(-)soman in diaphragm from 74.7, 70.5, 88.7 ng x g(-1) to 54.5 45.6, 50.0 ng x g(-1) at the time of 30, 90, 120 s after intoxication of soman subcutaneously vs. soman control respectively, but it had no influence on the concentration of free P(-)soman in brain. Isotope trace experiments showed that it could significantly increase the distribution amount of bound [3H]soman in mice plasma and small intestine during 0-120 min after mice received [3H]soman (0.544 GBq.119 microg x kg(-1), sc) compared to soman control group.

Effects of pretreatment with verapamil on the toxicokinetics of soman in rabbits and distribution in mouse brain and diaphragm.

The effects of verapamil on the elimination of soman in rabbit blood and distribution in mouse brain and diaphragm by determining the concentration of P(-)soman using the chirasil capillary gas chromatographic analysis method were studied in order to study the effects of verapamil on the metabolic detoxification of soman. Verapamil (10 mg kg(-1), im, 30 min before soman administration) could significantly reduce the concentration of P(-)soman in rabbit blood at 15, 60, 90, 120, 180 and 240 s after soman injection (43.2 microg kg(-1), iv) as compared to soman-treated control animal respectively. Toxicokinetics parameters showed verapamil could increase clearance rate from 20.8+/-1.51 to 44.3+/-7.0 ml kg(-1)s(-1) and reduce AUC of P(-)soman from 2.08+/-0.151 to 0.996+/-0.172 mg s l(-1). For experiments in mice, verapamil could reduce the concentration P(-)soman in diaphragm from 74.7, 70.5, 88.7 to 41.1, 39.0, 49.3 ng g(-1) at the time of 30, 90, 120 s after intoxication of soman subcutaneously vs. soman control respectively, but it had no influence on the concentration of free P(-)soman in brain. Verapamil accelerated the elimination of P(-)soman in the rabbits blood and reduced the distribution of P(-)soman in the mouse diaphragm.

Influence of nimodipine on elimination of soman in rabbit blood and distribution of [3H]soman in mice.

AIM: To investigate the effect of nimodipine on the elimination of soman in rabbit blood and distribution of [3H]soman in mice. METHODS: Chirasil capillary gas chromatographic analysis method with large volume injections was used to determine the concentration of C(+/-)P(-)soman in rabbit blood. [3H]soman trace method was used to study the effect of nimodipine on soman distribution in mice. RESULTS: Nimodipine (10 mg/kg, ip, 1 h pre-treated) could significantly reduce the concentration of C(+/-)P(-)soman in rabbit blood from (54+/-13) to (19+/-12) microg/L blood at 15 s after soman injection (43.2 microg/kg, iv). Nimodipine could increase clearance rate [CL(S)] from (20.8+/-1.5) to (31+/-11) mL/kg/s and reduce AUC of C(+/-)P(-)soman from (2.08+/-0.15) to (1.6+/-0.4) mg/s. Nimodipine (10 mg/kg, ip, 1 h pre-treated) treatment could significantly reduce the distribution amount of bound [3H]soman in plasma, brain, lung, and liver, moreover increased the distribution amount of bound [3H]soman in small intestine during 0-120 min after mice received [3H]soman (0.544 GBq*119 microg/kg, sc) compared to soman control group. CONCLUSION: Nimodipine might alter the distribution of soman and reduce the initial concentration of soman in rabbit blood, then accelerated the metabolic detoxication of soman.

Influence of portal vein and liver artery ligation on the toxicokinetics of soman in rabbits.

The portal vein, liver artery ligation treatment and the portal vein ligation treatment could increase the concentration of P(-) soman in rabbit blood 3.6-19.3 times as compared with soman control group at each time points after soman injection (43.2 microgkg(-1), i.v.). Toxicokinetics parameters showed that portal vein, liver artery ligation treatment and portal vein ligation treatment could reduce the clearance (CL) and distribution volume (V(d)). Meanwhile, they could significantly increase the AUC of soman in rabbits from 2.08+/-0.154 to 18.2+/-2.96 and 22.9+/-3.73 mg s l(-1), respectively. All these data showed that the liver and intestine play a very important role on elimination the free soman in rabbit's blood at high dosing of soman.