Metabolic studies urinary

Comparative Toxicokinetics. There are no data on the kinetics of diisopropyl methylphosphonate in humans. Studies in animals suggest that metabolism and urinary metabolite profiles are qualitatively similar among species. Additional studies would be useful in understanding the differences in metabolic rates in species and in determining which animal species is the most appropriate model for human exposure. 

We have conducted two human metabolic studies (5,6) to compare the effects of increasing phosphorus intake on calcium utilization in healthy young adults maintained at low (ca. 400 mg/day) and high (ca. 1200 mg/day) levels of calcium intake. Increasing dietary phosphorus, as orthophosphate, caused a slight reduction in fecal calcium and a substantial reduction in urinary calcium losses (Table III). 

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). 

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. 

Raunio H, Syngelma T, Pasanen M, Juvonen R, Honkakoski P, Kairaluoma MA, Sotaniemi E, Lang MA, Pelkonen O (1988) Immunochemical and catalytical studies on hepatic coumarin 7-hydroxylase in man, rat, and mouse, Biochem Pharmacol 37 3889-3895 Raunio H, Pokela N, Puhakainen K, Rahnasto M, Mauriala T, Auriola S, Juvonen RO (2008) Nicotine metabolism and urinary ehmination in mouse in vitro and in vivo, Xenobiotica 38 34 7... 

In swine, carbadox is metabolized rapidly to quinoxaline-2-carboxylic acid, with the intermediary formation of the aldehyde and the desoxy metabolite of the parent compound. Metabolism studies with radiolabeled carbadox showed that the parent compound and its three metabolites are present in plasma within hours after drug administration, but all four compounds can disappear within 24 h postdosing. The major urinary metabolite was shown to be the quinoxaline-2 -carboxylic acid, which was also excreted in the conjugated form. A -oxides were not found in urine. Feces also contained some quinoxaline-2-carboxylic acid but no unchanged carbadox (14). 

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. 

Steroid hormones by the application of isotope tracer techniques 3I8-321]. Lieberman and co-workers undertook urinary metabolic studies [304,325] by administration of isotopically labeled steroids followed by the determination of specific activities of urinary metabolites derived only from the administered substance. Mathematical analyses were performed by compartmentalization of the metabolism [385]. One- or two-compartment systems are most frequently used [304,306,384,386,387]. A compartment is defined as a particular species (e.g., dehydroepiandro-sterone sulfate) in a particular space (e.g., peripheral organ). It is assumed that a species entering a compartment mixes immediately with the whole compartment. Two factors were responsible for the institution of com-partmental analysis ... 

In addition to estimation on the basis of urinary metabolic studies, blood production rates of steroids can be estimated, after administration of isotopically labeled steroids, from the specific activity of the unchanged steroids in the blood. This method was extensively used by Tait and coworkers [322,324]. In 1966 a critical survey of steroid hormone metabolism was given by Baulieu [385]. 

M2. Marver, H. S., Studies on tryptophan metabolism. I. Urinary tryptophan metabolites in hypoplastic anemias and other hematologic disorders. J. Lab. Clin. Med. 58, 425-436 (1961). 

Analysis of In Vivo Fecal Metabolites by LC/MS. Besides the analysis of urinary metabolites, animal metabolism studies of course require characterization of fecal metabolic products. We have found that rapid analysis of fecal extracts can also be accomplished by LC/MS, although more extensive cleanup is required. A general procedure for the extraction and LC/MS analysis of rat fecal metabolites is given in Figure 14. This procedure can easily be completed in an afternoon to provide a preliminary indication of metabolite structures. Based on this information the appropriate derivatives can be prepared for additional characterization, if necessary. 

Metabolic studies with I-labeled Ethiodol indicated that the iodized oil was rapidly deiodinated by enzymes in tissues with the iodine appearing as inorganic iodide, which was excreted by the kidney. In humans, no more than 0.5%of the injected iodized oil was found in the blood at any one time, and the urinary excretion was less than 2.5% of the dose per day (159). The most serious side effect of the iodized oils is pulmonary or systemic embolization and granuloma formation (160), which is related to the particle size of the oily drops (150,157), but Kupffer cells can actively capture and phagocytize the iodized oil droplets (161). 

The metabolic pathways leading to the production of these urinary pyridinium metabolites are likely to be mediated by one or more forms of liver cytochrome P450. In vitro metabolic studies with rodent (Igarashi et al., unpublished results) and human (Usuki et al., submitted) microsomal preparations have demonstrated the NADPH-dependent oxidation of both HP and HPTP to HPP. Ongoing studies in the authors laboratory have shown that HPP and related pyridinium metabolites are present in brain tissues obtained from C57 black mice that had been treated with HPTP (Van der Schyf et al. 1994). Additionally, results obtained from intra-cerebral microdialysis, mitochondrial respiration, and rat embryonic mesencephalic cell culture studies suggest that HPP possesses MPP type neurotoxic properties (Rollema et al. 1992, 1994 Bloomquist et al. 1994). 

Metabolism studies with ethanolamines have been undertaken in the context of their use as industrial chemicals. Following PC and IV administration of Y-mcthyldicthanolaminc in the rat, a major fraction of the absorbed dose was excreted as unidentified urinary metabolites, with some unchanged A-methyldiethanolamine (Leung et al, 1996). Triethanolamine was excreted predominantly unmetabolized in mice following both IV and percutaneous administration (Stott et al, 2000). 

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