Toxicokinetics intravenous

IV. Intravenous Toxicokinetics of Soman and Sarin in Various Species... 

IV. INTRAVENOUS TOXICOKINETICS OF SOMAN AND SARIN IN VARIOUS SPECIES... 

M. J. van der Schans, J. P. Langenberg and H. P. Benschop, Intravenous toxicokinetics and metabolism of ( )-VXin the atropinized hairless guinea pig, NATO TG004 Meeting, 1999. 

Braeckman RA, Audenaert P, Willems JL, et al. 1983. Toxicokinetics of methyl parathion and parathion in the dog after intravenous and oral administration. Arch Toxicol 54 71-82. 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

Of particular interest in brevetoxin research are the diagnosis of intoxication and identification of brevetoxins and their metabolites in biological fluids. We are investigating the distribution and fate of radiolabeled PbTx-3 in rats. Three model systems were used to study the toxicokinetics and metabolism of PbTx-3 1) rats injected intravenously with a bolus dose of toxin, 2) isolated rat livers perfused with toxin, and 3) isolated rat hepatocytes exposed to the toxin in vitro. 

Reigner, B.G., R.A. Gungon, M.K. Hoag, and T.N. Tozer. 1991. Pentachlorophenol toxicokinetics after intravenous and oral administration to rat. Xenobiotica 21 1547-1558. 

Toxicokinetic studies in humans have demonstrated that coumarin is rapidly absorbed from the gastrointestinal tract after oral administration and extensively metabolized by the liver in the first pass, with only 2-6% reaching the systemic circulation intact (Ritschel etal., 1977, 1979 Ritschel Hofimann, 1981).The elimination of coumarin from the systemic circulation is rapid, the half-lives following intravenous doses of 0.125, 0.2 and 0.25 mg/kg bw being 1.82, 1.46 and 1.49 h [109, 88 and 89 min], respectively (Ritschel et a/., 1976). Coumarin is also extensively absorbed after dermal application. In one study with human subjects, some 60% of a 2.0-mg dose applied for 6 h was absorbed (reviewed in Lake, 1999). The percutaneous absorption of coumarin has also been demonstrated in vitro with human skin (Beckley-Kartey et al, 1997 Yourick Bronaugh, 1997). 

The toxicokinetics of coumarin have been studied in a number of species including rats (intraperitoneal, intravenous, oral and topical administration) (Hardt Ritschel, 1983 Ritschel Hussain, 1988), dogs (intravenous and oral) (Ritschel Grummich, 1981), gerbils (intraperitoneal) (Ritschel Hardt, 1983) and rhesus monkeys (intravenous and oral) (Ritschel et al, 1988). Generally, the half-life for the elimination of coumarin is similar in all species examined, being around 1-4 h (Lake, 1999). In rats, the toxicokinetics of coumarin are non-linear at intraperitoneal doses greater than 10 mg/kg bw (Hardt Ritschel, 1983). 

A three-compartment model has been described for the toxicokinetics of A-nitroso-diethanolamine studied in CD-COBS rats after a low intravenous dose (5 mg/kg bw). Blood levels of A-nitrosodiethanolamine reflected the levels in the liver, suggesting that the liver may not accumulate A-nitrosodiethanolamine. The overall elimination rate corresponded to a half-life of 5.77 h (Airoldi et al., 1984a). 

Valentine et al. (1997) studied the kinetics of epoxybutene and diepoxybutane in blood following intravenous administration to male Sprague-Dawley rats. The following toxicokinetic parameters were obtained for epoxybutene at 71, 143, 286 pmol/kg bw. 

Detailed toxicokinetic studies have been performed in both rats (Yuan et al., 1994) and mice (Reigner et al., 1992), comparing intravenous and gavage (and in rat feed) administration of pentachlorophenol. In mice, after either intravenous or oral administration, tlie elimination half-life was about 5-6 h. Only 8% of the dose (15 mg/kg bw) was excreted unchanged in urine, while 20% was excreted as tetrachlorohydroquinone and its conjugates. Sulfate conjugates represented 90% of the total conjugates of pentachlorophenol and tetrachlorohydroquinone. 

Ramesh, A., Hood, D.B., Inyang, F., Greenwood, M., Archibong, A., Knuckles, M.E., Nyanda, A.M. (2002). Comparative metabolism, bioavailability and toxicokinetics of benzo(a)py-rene in rats after acute oral, inhalation, and intravenous administration. Polycyclic Aromatic Compounds 22 969-80. 

Because deoxynivalenol (DON) commonly contaminates grains and swine are the most susceptible species, toxicokinetics for DON have been extensively studied in this species (Coppock et al, 1985b Prelusky et al, 1988, 1990 Prelusky and Trenholm, 1991 Goyarts and Danicke, 2006). Intravenously administered DON (1 mg/kg body weight) distributed rapidly to all tissues and body fluids, and declined to neghgible levels within 24 h except in urine and bile... 

Van der Schans, M.J., Lander, B.J., Van der Wiel, H., Langenberg, J.P., Benschop, H.P. (2003). Toxicokinetics of nerve agent ( )-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration. Toxicol. Appl. Pharmacol. 191 48-62. 

Most of the information on the toxicokinetics of dinitroanilines pertains to 2,4-dinitroaniline. Dinitroanilines are highly toxic to humans and are well absorbed from all routes of exposure. Nine metabolites were detected in rats administered [ C]2,4-dinitroaniline orally or intravenously. 2,4-Dinitrophenylhydroxylamine was the main metabolite and was excreted in the urine as the sulfate conjugate and in bile as the glucuronide. Amine hydroxylation and sulfation of 2,4-dinitroaniline are probable detoxification processes that occur rapidly and facilitate clearance. 

Alcohol also has the potential for enhancing the toxicity of nitrobenzene however the toxicokinetic mechanism is not known. It is clear, however, that alcohol does not simply enhance the absorption of nitrobenzene. When alcohol was given orally and nitrobenzene is given intravenously, there was increased toxicity in rabbits. Alcohol also enhanced the neural toxicity of nitrobenzene in rabbits when nitrobenzene was applied to the skin (Matsumaru and Yoshida 1959). 

Toxicokinetics of the nerve agent (+/-)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration. Toxicol Appl Pharmacol, 191, 48-62. 

Spruit HET, Langenberg JP, Trap HC et al. (2000). Intravenous and inhalation toxicokinetics of sarin stereoisomers in atropinized guinea pigs. Toxicol Appl Pharmacol, 169, 249-254. 

Figure 8. Calculated human AChE activities (left-hand side) after intravenous cyclosarin and simultaneous intramuscular oxime injection. The changes in AChE activity were calculated by using the toxicokinetic data of (-)-sarin (Spruit et al., 2000) and human pharmacokinetic data of the oximes (Worek et al., 2005) for 1, 2 and 3 autoinjector equivalents (AIs) of obidoxime (1 AI = 250 mg), 2-PAM (1 AI = 600 mg) and HI 6 (1 AI = 500 mg) and exposure to 0.8 x LD50 cyclosarin ((—), 1...

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