Metabolism studies in laboratory animals

At the completion of the study, the data obtained should be evaluated in relationship to exposure (dermal and inhalation), absorption (urinary metabolites), effects (ChE inhibited), acute, chronic, and metabolic studies in laboratory animals. These findings should then be evaluated and discussed in relation to existing or proposed labeling or regulations. 

Toxicology studies in vivo in laboratory animals and in vitro studies for genotoxicity In vitro studies to establish spectrum of activity and potency of AMDs Pharmacokinetic studies in laboratory animals and target species Metabolism studies in laboratory animals and target species Residue depletion studies in target species... 

VICH GL 47, MRK—Comparative Metabolism Studies. Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Animals, Comparative Metabolism Studies in Laboratory Animals, Draft 1, Nov. 2009 (available at http //www.vichsec.org/en/guide lines3.htm accessed 11/30/10). 

Metabolism studies in laboratory animals, including the rat, indicate that saccharin is not metabolized (Byard and Golberg, 1973 Mathews et al., 1973 Mineglshi et al., 1972). Saccharin is readily absorbed from the gastrointestinal tract and is rapidly excreted by the kidneys. Saccharin does not form covalently bound adducts with DNA in the bladder of the rat in an assay that would have detected one mole of saccharin per 10 moles of DNA phosphate (Lutz and Schlatter, 1977). By contrast, aflatoxln B has a covalent binding index in liver of 10,300 (Lutz, 1979) compared to a value for saccharin in the bladder of less than 0.05 (Lutz and Schlatter, 1977). Saccharin also appears to be nonmutagenic (Cranmer, 1980). 

The results of metabolism studies with laboratory animals and livestock indicate that endosulfan does not bioconcentrate in fatty tissues and milk. Lactating sheep administered radiolabeled endosulfan produced milk containing less than 2% of the label. Endosulfan sulfate was the major metabolite in milk (Gorbach et al. 1968). A half-life of about 4 days was reported for endosulfan metabolites in milk from survivors of a dairy herd accidentally exposed to acutely toxic concentrations of endosulfan endosulfan sulfate accounted for the bulk of the residues detected in the milk (Braun and Lobb 1976). No endosulfan residues were detected in the fatty tissue of beef cattle grazed on endosulfan-treated pastures for 31-36 days (detection limits of 10 ppm for endosulfan, 40 ppm for endosulfan diol) the animals began grazing 7 days after treatment of the pastures. Some residues were detected in the fatty tissue of one animal administered 1.1 mg/kg/day of endosulfan in the diet for 60 days. No endosulfan residues were... 

Leong, B.K.J., Coombs, J.K., Petzold, E.N. and Hanchar, A.J. (1988). A dosimetric endotracheal nebulization technique for pulmonary metabolic disposition studies in laboratory animals. Inhal. Toxicol, (premier issue) 37-51. 

More than 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using doses much higher than people could possibly consume. The safety profile was further confirmed in studies of several human subpopulations, including... 

Munro et al (1993) reviewed metabolic and pharmacokinetic studies in laboratory animals which showed that PHAs are rapidly absorbed, and that once absorbed these substances or their metabolites are distributed to various organs such as the liver, kidneys, intestine, stomach, and lungs. PHAs undergo metabolic activation or detoxication and are eliminated through either the urine or feces to more or less the same degree. The amounts of PHAs or their metabolites in tissues have been reported to decline to undetectable levels within 72 hours however, residual levels have been detected in both liver and intestines (Bergman, 1985 Alldrick and Rowland, 1988 Gooderham et a/., 1991). 

Absorption, Distribution, Metabolism, and Excretion. Studies in laboratory animals indicate that di- -butyl phthalate given orally is readily absorbed, mainly as the metabolite mono- -butyl phthalate, and subsequently, is rapidly excreted. Limited data exist regarding inhalation and dermal absorption. Studies on the absorption and metabolism of di- -butyl phthalate by the inhalation and dermal routes are needed to evaluate human health risk by these routes of exposure. 

Examples of PLC with autoradiography detection include the published studies on labeling of l- H-PAF-aceter [25] diazinon and related compounds from plant material [26] metabolic fate of triamcinolone acetonide in laboratory animals [27] synthesis of 4-S-cysteaminyl-[U- " C]phenol antimelanoma agent [28] radiolabeled... 

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. 

Today, in the United States, the FDA is responsible for examining safety and efficacy data before an antibiotic or synthetic chemical may be commercialized for livestock use. This includes studies on formulations, product stability, conventional and genetic toxicity, environmental safety, metabolism, residue studies in target animals, studies on antibiotic resistance in gut microflora and on salmonella shedding in target animals. Similar requirements are part of registering these products in overseas markets. In general, after a product is discovered in the laboratory, many... 

Results of metabolic and toxicokinetic studies in laboratory and target animals... 

Death. Aluminum is not thought to be life-threatening to healthy humans. Studies of people receiving extremely high doses of oral aluminum in antacids have not shown any human deaths from aluminum. However, in the past, aluminum-related deaths have been reported for persons with renal disease dialyzed with aluminum -containing solutions, uremic patients exposed to dietary aluminum hydroxide to treat hyperphosphatemia and sodium citrate to correct metabolic acidosis (Kirschbaum and Schoolwerth 1989), and workers exposed by inhalation to fine powders of aluminum metal. Only very large doses (hundreds of mg/kg) of aluminum cause death in laboratory animals. 

A few of the factors shown in the outer circle of Fig. 1 have not been studied in human subjects. Those have been demonstrated in laboratory animals to affect drug metabolism and disposition. 

Knapp DR (ed) (1979) Handbook of Analytical Derivatisation Reactions. Wiley, New York, p 2 Ribeiro W, Muscara MN, Martins AR et al. (1996), Bioequivalence study of two enalapril maleate tablet formulations in healthy male volunteers. Eur JClin Pharmacol 50 399-405 Tocco DJ, De Luna FA, Duncan AEW et al. (1982), The physiological disposition and metabolism of enalapril maleate in laboratory animals. Drug Metab Disp 10 15-19... 

Additional data are needed to better define the exposure of humans and, in the context of animal toxicity studies, of laboratory animals. Because JP-8 is a complex mixture of chemicals that differ in volatility, solubility, metabolic rate and pathway, and rate and route of elimination from the body, dosimetry of critical components of the mixture at critical sites in the body is important to enhance the quality of risk assessment. The fact that human exposures can involve liquid fuel, aerosolized fuel, and vapor, by inhalation, dermal, and oral routes of exposure makes it difficult to accurately predict the internal dose of JP-8 and its components. 

---