Amounts Of Metabolites In Urine Research Articles

Metabolism of propyrisulfuron: 14C excretion, 14C concentration in plasma and tissues, and amount of metabolites in rats

1. Metabolism of a novel sulfonylurea herbicide, propyrisulfuron [1-(2-chloro-6-propylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-3-(4,6-dimethoxypyrimidin-2-yl)urea] labeled at the C-1 position of the propyl group and C-5 position of the pyrimidine ring with 14C was investigated after a single oral administration in male and female rats.2. Administered 14C was excreted into the urine (5.7–29.8%) and feces (64.6–97.4%), respectively. 14C concentration in plasma reached a maximum level at 4 to 12 h post-administration and then decreased rapidly with a biological half-life of approximately 23 to 32 h. Total 14C residues in the whole body were <0.1–1.4%, suggesting that the residues were not accumulated in the tissues.3. The amount of metabolites in urine, feces, and bile were quantified using high-performance liquid chromatography (HPLC). There were no differences in metabolites found between male and female rats.4. The absorption for the low dose (5 mg/kg) and the high dose (1000 mg/kg) was estimated to be approximately 90% and 20%, respectively, suggesting a saturable absorption.5. The plasma protein binding in male and female rats was ≥98.8%, suggesting that propyrisulfuron had a strong affinity to plasma proteins.

Exposure reconstruction using a physiologically based toxicokinetic model with cumulative amount of metabolite in urine: a case study of trichloroethylene inhalation

The use of a physiologically based toxicokinetic (PBTK) model to reconstruct chemical exposure using human biomonitoring data, urinary metabolites in particular, has not been fully explored. In this paper, the trichloroethylene (TCE) exposure dataset by Fisher et al. (Toxicol Appl Pharm 152:339–359, 1998) was reanalyzed to investigate this new approach. By treating exterior chemical exposure as an unknown model parameter, a PBTK model was used to estimate exposure and model parameters by measuring the cumulative amount of trichloroethanol glucuronide (TCOG), a metabolite of TCE, in voided urine and a single blood sample of the study subjects by Markov chain Monte Carlo (MCMC) simulations. An estimated exterior exposure of 0.532 mg/l successfully reconstructed the true inhalation concentration of 0.538 mg/l with a 95% CI (0.441–0.645) mg/l. Based on the simulation results, a feasible urine sample collection period would be 12–16 h after TCE exposure, with blood sampling at the end of the exposure period. Given the known metabolic pathway and exposure duration, the proposed computational procedure provides a simple and reliable method for environmental (occupational) exposure and PBTK model parameter estimation, which is more feasible than repeated blood sampling.

Alpha 2u-globulin nephropathy and carcinogenicity following exposure to decalin (decahydronaphthalene) in F344/N rats.

Decalin (decahydronaphthalene) is a widely used industrial solvent known to cause male rat-specific alpha2u-globulin nephropathy. In this project, 13-week and two-year inhalation studies of decalin were conducted consecutively in both sexes of F344/N rats. The key objectives were to (1) characterize the 13-week toxicity of decalin in rats, with an emphasis on nephropathy in males; (2) compare the kidney concentrations of decalin, 2-decalone, and alpha2u-globulin in males over 2 to 13 weeks of decalin exposure; and (3) correlate male rat nephropathy observed in the 13-week study with renal carcinogenicity in the two-year study. F344 rats (M/F) were exposed via whole-body inhalation to 0, 25, 50, 100, 200, or 400 ppm decalin for 13 weeks. Urine was collected at weeks 2 and 6 for creatinine and decalol analyses and at week 12 for clinical urinalysis. Right kidneys were collected from male rats at weeks 2 and 6 and from both sexes at week 13, homogenates were prepared using the whole kidney, and these homogenates were analyzed for alpha2u-globulin, decalin, and 2-decalone. Left kidneys were evaluated for histopathology and cell proliferation utilizing a proliferating cell nuclear antigen technique and counting proximal renal tubular epithelial cells to determine cell labeling indices. Necropsies and histopathologic evaluations were performed at week 13. Decalin exposure caused increases in kidney weight, urinalysis parameters (protein, AST, LDH), kidney alpha2u-globulin concentration, and proximal convoluted renal tubular cell proliferation in males. These changes were accompanied by microscopic lesions (accumulation of hyaline droplets in cortical tubules, regeneration of proximal tubular epithelium, and granular casts in medullary tubules) clearly linked to alpha2u-globulin nephropathy. Both decalin and 2-decalone were related to increased alpha2u-globulin in male kidneys. Kidney concentrations of decalin, 2-decalone, and alpha2u-globulin in exposed females were negligible, while females excreted greater amounts of decalol metabolites in urine than males at weeks 2 and 6. There were no exposure-related microscopic lesions in females. For chronic exposure, F344 rats were exposed via whole-body inhalation to 0, 25, 50 (males only), 100, or 400 ppm decalin for two years. Chronic exposure induced a spectrum of nonneoplastic and neoplastic lesions in the renal cortex of males, ranging from regenerative lesions of chronic nephropathy to tubular carcinomas. Incidences of renal tubular adenoma, tubular carcinoma, combined tubular adenomas and carcinomas, cortical tubular hyperplasia, hyaline droplet accumulation, hyperplasia of pelvic epithelium, and mineralization in renal papilla were increased in exposed males compared to controls. There was a clear increase in the mean severity of chronic nephropathy in decalin-exposed males. It was concluded that the carcinogenic effect on the renal cortical epithelium of male rats exposed to decalin was related to increased turnover of this epithelium, resulting from the cytotoxic effects of alpha2u-globulin accumulation in the renal cortical tubular cell cytoplasm.

Human dose-excretion studies with the pyrethroid insecticide cyfluthrin : urinary metabolite profile following inhalation

1. Nine male volunteers were exposed to the pyrethroid insecticide cyfluthrin. The study was performed in an exposure room, where an aerosol containing cyfluthrin was sprayed to obtain atmospheres with mean cyfluthrin concentrations of 160 and 40 μg/m3. Four volunteers were exposed for 10, 30 and 60 min at 160 μg/m3 and another five volunteers were exposed for 60 min at 40 μg/m3. For 160 μg/m3 exposure urine samples were collected before and immediately after exposure as well as for the periods 1-2, 2-3, 3-4, 4-5, 5-6, 6-12 and 12-24 h after exposure. For 40 μg/m3 exposure urine samples were collected before and 2 h after exposure. 2. The main urinary cyfluthrin metabolites, cis-trans-3-(2,2-dichlorovinyl)- 2,2- dimethylcyclopr opane carboxylic acid (DCCA) and 4-fluoro-3-phenoxybenzoic acid (FPBA), were determined. The limit of detection (LOD) for all metabolites was 0·0025 μg in an urine sample of 5 ml (0·5 μg/l). After inhalative exposure of 40 μg cyfluthrin/m3 air for 60 min, the amount of metabolites in urine collected in the first 2 h after exposure was less than the LOD, namely 0·14 μg for cis-DCCA, 0·15-0·28 μg for trans-DCCA and 0·12-0·23 μg for FPBA. 3. Of the metabolites, 93% was excreted within the first 24 h (peak excretion rates between 0·5 and 3 h) after inhalative exposure of 160 μg/m3. The mean half-lives were 6·9 h for cis-DCCA, 6·2 h for trans-DCCA and 5·3 h for FPBA. 4. The mean trans-:cis-DCCA ratio was 1·9 for the time course as well as for each subject. 5. The amount of metabolites in urine depends on the applied dose, on the exposure time and shows interindividual differences.

Studies on drug metabolism by use of isotopes XXIV —Determination of 3-phenylpropyl carbamate metabolites using stable isotope labelling with deuterium or carbon-13

Metabolism of 3-phenylproply carbamate was investigated by using a stable isotope tracer technique. 3-Phenylpropanol, 3-hydroxy-3-phenylpropanol, 3-hydroxy-3-phenylpropyl carbamate, 2,3-dihydroxy-3-phenylproply carbamate, benzoic acid and hippuric acid were identified as the rat urinary metabolites. Using the dilution analysis, the amounts of metabolites in urine and faeces in rat and man were determined. In rats, 2,3-dihydroxy-3-phenylproply carbamate and 3-phenylpropanol glucuronide were excreted into the urine as the major metabolites of this drug. On the other hand, in man, the major metabolite was hippuric acid and about 30% of the administered dose was excreted as hippuric acid in the 24 h urine. The tracer technique using a singly labelled drug with carbon-13 employed in the present study provided a reliable methods for the analysis of drug metabolites and was comparable with the tracer technique using a multilabelled drug with deuterium.

Active metabolites of isoxazolylpencillins in humans.

Metabolites of the isoxazolylpenicillins that still possessed antibacterial activity were shown to be present in urine and serum. In healthy subjects, the amounts excreted in urine were low; 10 to 23% of the excreted penicillin activities represented the metabolites. The highest amount of metabolite in urine was found for oxacillin, and the lowest was found for flucloxacillin. No extreme differences in the amounts of metabolite excreted were observed when the compounds were administered orally or intravenously. In one healthy subject metabolite levels were estimated for cloxacillin in serum. Very low levels were found, i.e., about 9% of the activity. In subjects with highly impaired renal function, the metabolite may represent up to 50% of the total level of penicillin in serum. The antibacterial activities of the different metabolites were of the same order of magnitude as those of the respective parent compounds. Also, the activity against benzylpenicillin-resistant staphylococci was retained. It is not likely that the formation of the active metabolites should influence therapeutic results.