Intravenous and inhalation toxicokinetics of sarin stereoisomers in atropinized guinea pigs.

We report the first toxicokinetic studies of (+/-)-sarin. The toxicokinetics of the stereoisomers of this nerve agent were studied in anesthetized, atropinized, and restrained guinea pigs after intravenous bolus administration of a dose corresponding to 0.8 LD50 and after nose-only exposure to vapor concentrations yielding 0.4 and 0.8 LCt50 in an 8-min exposure time. During exposure the respiratory minute volume and frequency were monitored. Blood samples were taken for gas chromatographic analysis of the nerve agent stereoisomers and for measurement of the activity of blood acetylcholinesterase (AChE). In all experiments, the concentration of (+)-sarin was below the detection limit (<5 pg/ml). The concentration-time profile of the toxic isomer, i.e., (-)-sarin, after an intravenous bolus was adequately described with a two-exponential equation. (-)-Sarin is distributed ca. 10-fold faster than C(-)P(-)-soman, whereas its elimination proceeds almost 10-fold slower. During nose-only exposure to 0.4 and 0.8 LCt50 of (+/-)-sarin in 8 min, (-)-sarin appeared to be rapidly absorbed. The blood AChE activity decreased during the exposure period to ca. 15 and 70% of control activity, respectively. There were no effects on the respiratory parameters. A significant nonlinearity of the toxicokinetics with dose was observed for the respiratory experiments.

Inhalation toxicokinetics of soman stereoisomers in the atropinized guinea pig with nose-only exposure to soman vapor.

The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman were studied in anesthetized, atropinized guinea pigs for nose-only exposure to soman vapor. During exposure the respiratory minute volume (RMV) and respiratory frequency (RF) were monitored. Blood samples were taken for chiral gas chromatographic analysis of the concentrations of nerve agent stereoisomers and for measurement of the progressive inhibition of acetylcholinesterase (AChE). The animals were exposed for 4-8 min to 0.4-0.8 LCt50 of C(+/-)P(+/-)-soman. Concentrations of the P(-)-isomers increased rapidly during exposure, up to several nanograms per milliliter of blood. Mathematical equations describing the concentration-time courses of the P(-)-isomers were obtained by nonlinear regression. The kinetics were mathematically described as a discontinuous process, with a monoexponential equation for the exposure period and a two-exponential equation for the postexposure period. The absorption phase of C(+)P(-)-soman lagged behind that of the C(-)P(-)-isomer, presumably due to preferential covalent binding at as yet unidentified binding sites. The terminal half-life observed after nose-only exposure is longer than that observed after an equitoxic iv bolus administration, which suggests the presence of a depot in the upper respiratory tract from which absorption continues after termination of the exposure. Two types of nonlinearity of the toxicokinetics were observed, i.e., with dose and with exposure time. The AChE activity was rapidly inhibited during exposure to the nerve agent vapor. There were no soman-related effects on RMV and RF. The toxicokinetics of the soman stereoisomers observed for nose-only exposure are compared with those determined for iv bolus and sc administration.

Absorption of bismuth from several bismuth compounds during in vivo perfusion of rat small intestine.

Evaluation of the amount of bismuth (Bi) absorbed from the gastrointestinal tract is important for assessment of the possible risks associated with the use of Bi compounds in the treatment of gastrointestinal disorders. We compared the absorption of Bi from media containing the equivalent of 1 g of elemental Bi from either Bi subnitrate (BSN), Bi subsalicylate (BSS), colloidal Bi subcitrate (CBS), Bi chloride (BiCl3), or Bi citrate (BCit) by an in vivo perfusion system of rat small intestine. The intestinal absorption was < 1% for all compounds, but higher from BCit and CBS than from BSN, BSS, and BiCl3. The dose dependency of Bi absorption from both CBS and BiCl3 in citrate buffer showed a nonlinear relationship between the concentration of Bi in perfusate and the concentration of Bi in blood after 60 min.

Analysis for bismuth in tissue by electrothermal atomic absorption spectrometry.

We developed a simple method for the analysis of bismuth (Bi) in biological tissue, using wet digestion for sample pretreatment. Bi was determined by electrothermal atomic absorption spectrometry with platinum as a matrix modifier to decrease the volatility of Bi. The furnace program included a gas stop for sensitivity enhancement. Analytical performance was established for Bi in kidney, liver, brain, and bone. As little as 25 ng/g wet weight can be detected in the most concentrated digests. Homogenization of bone was necessary before digestion, and its matrix showed the strongest interference. In rats exposed orally to colloidal bismuth subcitrate for 14 days, the metal could be detected in liver, kidney, and spleen but not in brain and bone. In the tissues of 12 patients who died from non-Bi-related causes, no Bi were present in kidney in the other 2.

Development of a therapeutic procedure for bismuth intoxication with chelating agents.

Although bismuth poisoning is still a rare phenomenon, the increasing use of bismuth-containing drugs warrants a systematic approach to the treatment of bismuth overdose. An effective method of enhancing the elimination of toxic amounts of bismuth from the body has not been reported. Therefore we performed a study to select the best chelator to treat bismuth poisoning. Dimercaprol (BAL), meso-2,3-dimercaptosuccinic acid (DMSA), D,L-2,3-dimercapto-propane-I-sulfonic acid (DMPS), D-penicillamine (D-PEN), N-acetyl-D,L-penicillamine (Ac-PEN), thiopronine (TP), sodium-calcium edetate (EDTA) and deferoxamine (DFO) were tested with an in vitro model of equilibrium dialysis and an in vivo model of rats poisoned with bismuth. The rats (n = 6 per substance tested) were treated with the chelators in intraperitoneal doses of 250 mumol/kg.day for 3 consecutive days. Afterward, tissue and blood samples were collected. Bismuth concentrations were determined with electrothermal atomic absorption spectrometry in serum, buffer, urine, blood, brain, kidney, liver, spleen, and bone. Using in vitro results, we constructed a ranking of chelating agents; it appeared not to predict the in vivo results. The dithiol compounds (DMPS, DMSA and BAL) were effective in most organs (especially in kidney and liver) resulting in a higher elimination of bismuth in urine by DMPS and BAL. BAL was the only chelator effective in lowering brain bismuth concentrations, whereas treatment with EDTA resulted in increased brain bismuth levels. For D-PEN and DFO, no effects could be demonstrated. For clinical practice, DMSA and DMPS may well be the chelators of choice; the application of BAL should be reserved for very severe cases of poisoning because of its own toxicity.

Analysis of bismuth in serum and blood by electrothermal atomic absorption spectrometry using platinum as matrix modifier.

Bismuth-containing medicines have been used for years, but there is a lack of clinically applicable methods for measuring bismuth in body fluids. We describe a sensitive, accurate and precise method for analysis of bismuth in blood and serum, which is suitable both for monitoring purposes and for further investigations into the biokinetics and safety of bismuth. Bismuth was quantitated with electrothermal atomic absorption spectrometry with Zeeman background correction. In the furnace programme a cool-down step was introduced and platinum was used as a matrix modifier. Recovery for 40 micrograms/l is 93.7 +/- 4.6% (mean +/- SD) from serum and 92.8 +/- 5.4% from blood; within-day precision (n = 10) at 40 micrograms/l is 3.2% for serum and 4.2% for blood. Day-to-day precision at 40 micrograms/l (n = 10) was 4.5% for serum and 4.0% for blood. The detection limit is 0.7 microgram/l for serum and 1.0 microgram/l for blood. Blood samples have to be collected in glass tubes and stored at -20 degrees C.