Rats, metabolism studies

Literature data on the depletion of levamisole residues from edible animal products concern only the parent drug (33). It appears, however, that the metabolism of levamisole in food-producing animals is qualitatively similar to that in rats, since limited data from swine (34) and goats (35) are generally consistent with those observed for rats. Metabolism studies in rats using radiolabeled levamisole showed extensive metabolism of levamisole, with at least 50 metabolites identified in some samples of urine from treated rats. 

In the rat studies a major additional metabolic pathway was discovered, which had not been found in soils, i.e. the hydroxylation of the intact diflubenzuron molecule leading to the three different metabolites indicated in the Figure, which were found partly as conjugates. These hydroxy derivatives accounted for almost all the metabolites in the bile and for about half the metabolites in the urine. The rat metabolism studies will be published more extensively elsewhere (22.) ... 

Results of the rat metabolism studies indicate that, as in cattle, the primary route of metabolism of flunixin is via oxidation of the aromatic ring system(s) and the methyl group on the phenyl ring. Flunixin and the two hydroxylated metabolites,... 

Ractopamine HCl. The C ractopamine HCl was synthesized at Lilly Research Laboratories. The material was uniformly labeled either in one or the other benzene rings. Radiochemically equivalent amounts of each label were mixed with unlabeled ractopamine HCl and used in the studies. The specific activity of the C ractopamine HCl dose was 0.25 p.Ci/mg in the swine residue studies, 0.5 p.Ci/mg in the balance-excretion study, and 2.0 iCi/mg in the swine, dog, and rat metabolism studies. 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Gagne J, Brodeur J. 1972. Metabolic studies on the mechanism of increased susceptibility of weanling rats to parathion. Can J Physiol Pharmacol 50 902-915. 

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. 

Only limited metabolic studies have been carried out on NPIP. It undergoes a-hydroxylation by rat liver microsomes to give 5-hydroxypentanal, a process analogous to the formation of... 

In studies in rats and mink that used more than one dose, the area under the plasma-IMPA concentration time curves indicated that at high doses the principal pathway for the conversion of diisopropyl methylphosphonate to IMPA was saturated (Bucci et al. 1992). In rats, metabolism was saturated at an oral dose of 660 mg/kg, but not at 66 mg/kg in mink, an oral dose of 270 mg/kg caused metabolic saturation which did not occur at 27 mg/kg. 

Finally, we have studied the metabolism of a series of PAH with decreasing IP. In these metabolic studies with Aroclor-induced rat liver microsomes, the formation of quinones was measured in the presence of NADPH or cumene hydroperoxide as cofactor. 

Courtney, K.D., J.P. Putnam, and J.E. Andrews. 1978. Metabolic studies with TCDD (dioxin) treated rats. Arch. Environ. Contain. Toxicol. 7 385-396. 

Renner, G. and C. Hopfer. 1990. Metabolic studies on pentachlorophenol (PCP) in rats. Xenobiotica 20 573-582. 

Extensive metabolism studies carried out mainly in rats and mice show that pyrethroids are metabolized by oxidation and ester cleavage, which are mediated by CYP isoforms and carboxylesterases, respectively. CYP isozymes and carboxylesterases responsible for the metabolism are reviewed below. 

These in vivo and in vitro human metabolism studies indicate that pyrethroids undergo rapid metabolism and elimination as observed in rats, and qualitative metabolic profiles (e.g., kinds of metabolites) of pyrethroids are assumed to be almost the same between humans and rats, suggesting that a large database of animal metabolism of pyrethroids could provide useful information for the evaluation of behavior of pyrethroids in humans. Nowadays, human pesticide dosing studies for regulatory propose are severely restricted in the US, and thus detailed comparison of in vitro metabolism (e.g., metabolic rate constants of pathways on a step-by-step basis) using human and animal tissues could be an appropriate method to confirm the similarity or differences in metabolism between humans and animals. 

Three different pathways are associated with the metabolism of disulfoton (I) oxidation of the thioether sulfur to produce sulfoxides and sulfones (2) oxidation of the thiono sulfur to produce the oxygen analogs and (3) hydrolysis of the P-S-C linkage to produce the corresponding phosphorothionate or phosphate (WHO 1976) (see Figure 2-3). These pathways have been elucidated from data obtained in humans exposed to disulfoton and from in vivo and in vitro metabolism studies in rats and mice. 

Results of DEHP metabolism studies in vivo and in vitro, when considered together, suggest that the major route of metabolism for DEHP in fish consists of hydrolysis to the monoester. The monoester may then be conjugated with glucuronic acid, or further hydrolyzed to phthalic acid, or the remaining sidechain may be oxidized. This is similar to the reported pathway for DEHP metabolism in rats. In rats, dietary DEHP is to a large extent hydrolyzed to the monoester before absorption from the gut. When the monoester is administered orally, the urinary metabolites found are the same as those found after administration of DEHP (17). 

Among the requirements for registration of pesticides in the United States, the 1978 guidelines proposed by the U.S. Environmental Protection Agency (3) list general metabolism studies "in at least one mammalian species, preferably the laboratory rat. .." Although similar tests have been conducted on other terrestrial species with increasing frequency, the small rodents have remained the principal source of metabolism data from intact animals. 

Nuclear magnetic resonance (NMR) spectroscopy of untreated biological fluids has been used successfully in metabolic studies of penicillins. Connor et al. [153] used this method to investigate the metabolism and urinary excretion of ampicillin and amoxycillin in humans and rats. In addition to the metabolites 5.49 and 5.50, they detected a dimer of amoxycillin (5.51) in rat urine. 

A simple cyclic diester of carbonic acid is ethylene carbonate (7.96), a chemical with a toxicity profile resembling that of ethylene glycol (7.97). Metabolic studies have confirmed that ethylene carbonate is hydrolyzed very rapidly to ethylene glycol (whose oxidation is discussed in Chapt. 2 in [7]) and C02. Indeed, rats given an oral dose of ethylene carbonate did not excrete the unchanged xenobiotic in detectable amounts, and blood levels of the diester were ca. 100-fold smaller than those of ethylene glycol [178],... 

There are a few data in the literature to suggest that the hydrolysis of aliphatic nitriles occurs in mammals, but only as a minor or even undetectable pathway in competition with oxidative denitrilation. For example, benzyl cyanide (11.80, Fig. 11.12) undergoes cytochrome P450 catalyzed hydroxy-lation to mandelonitrile (11.81), from which cyanide and benzaldehyde are produced, the latter being oxidized to benzoic acid (11.83) [118]. However, a careful metabolic study of mandelonitrile has shown that, in the rat, this pathway accounts for ca. 90% and not 100% of the dose [122], Only ca. 10% of orally administered benzyl cyanide was converted to mandelic acid (11.82, Fig. 11.12) by hydrolysis of the CN group. 

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