Metabolites urinary

C21H36O2. M,p. 238°C. There are four isomeric pregnane-3,20-diols differing only in the orientation of the hydroxyl groups at positions 3 and 20 and with the 5/ configuration. Only the 3a,20a occurs naturally. It is formed by reduction of progesterone in the liver and is the chief urinary metabolite of it, being... 

Synthesis of the Major Human Urinary Metabolite of Prostaglandin D2... 

The clinical measurement of prostaglandin D2, produced in the body by activation of immune-active cells, required the synthesis of the major urinary metabolite. A synthesis was developed starting with the standard intermediate for PG synthesis. 

Histamine is a critical mediator in anaphylactic reactions. It is a diamine produced by decarboxylation of the amino acid histidine in the Golgi apparatus of mast cells and basophils. Once secreted, it is rapidly metabolized by histamine methyltransferase [2]. Plasma histamine levels are elevated in anaphylaxis, reaching a concentration peak at 5 min and declining to baseline by 30-60 min [3]. Therefore, histamine samples for assessing an anaphylactic reaction should be obtained within 15 min of the onset of the reaction. Urinary metabolites of histamine may be found for up to 24 h. 

Glycine participates in the biosynthesis of heme, purines, and creatine and is conjugated to bile acids and to the urinary metabolites of many drugs. 

Name Alternative Designation Enzymatic Defect Urinary Metabolites... 

An update of a previous study (Axelson et al. 1978), Axelson (1986) evaluated an expanded cohort of 1,424 men (levels of trichloroethylene exposure inferred from measured urinary metabolite concentrations) and found a significant increase in incidences of bladder cancer and lymphomas, and a lower than expected incidence of total cancer mortality. A further update of this work (Axelson et al. 1994) expanded the cohort to include 249 women, tracking cancer morbidity over 30 years, and found no correlation between exposure concentration or exposure time and cancer incidence at any site. The highest standardized incidence ratio noted in this study was 1.56 (95% Cl of 0.51-3.64) for 5 cases of non-Hodgkin s lymphoma observed in men. Although four of these cases occurred in persons exposed for at least 2 years, and 3 cases had a latency of 10 years or more, urinary levels of TCA showed that 4 of the 5 cases were exposed to the lowest levels of trichloroethylene (urinary levels of TCA 0-49 mg/L). The study authors mentioned that a urinary TCA level below 50 mg/L corresponds to a trichloroethylene exposure concentration of about 20 ppm. The study authors concluded that "this study provides no evidence that trichloroethylene is a human carcinogen, i.e., when the exposure is as low as for this study population."... 

Following inhalation exposure to trichloroethylene in humans, the unmetabolized parent compound is exhaled, whereas its metabolites are primarily eliminated in the urine. Excretion of trichloroethylene in the bile apparently represents a minor pathway of elimination. Balance studies in humans have shown that following single or sequential daily exposures of 50-380 ppm trichloroethylene, 11% and 2% of the dose was eliminated unchanged and as trichloroethanol, respectively, in the lungs 58% was eliminated as urinary metabolites and approximately 30% was unaccounted for (Monster et al. 1976, 1979). Exhaled air contained notable concentrations of trichloroethylene 18 hours after exposure ended because of the relatively long half-life for elimination of trichloroethylene from the adipose tissue (i.e., 3.5-5 hours) compared to other tissues (Fernandez et al. 1977 Monster et al. 1979). 

The primary urinary metabolites of trichloroethylene in humans are trichloroethanol, trichloroethanol glucuronide, and TCA (Monster et al. 1979 Nomiyama and Nomiyama 1971 Sato et al. 1977). The halftime for renal elimination of trichloroethanol and trichloroethanol glucuronide has been determined in several studies to be approximately 10 hours following trichloroethylene exposure (Monster et al. 1979 Sato et al. 1977). The urinary excretion of TCA is much slower, and data from several studies indicate that the halftime of urinary TCA is approximately 52 hours because the metabolite is very tightly and extensively bound to plasma proteins (Monster et al. 1976 Sato et al. 1977). 

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

The metabolism of trichloroethylene, as measured by the levels of excreted urinary metabolites, differs significantly between men and women, although study results are inconsistent (Inoue et al. 1989 Kimmerle and Eben 1973b Nomiyama and Nomiyama 1971). It does appear, however, that women excrete more urinary TCA than do men (Kimmerle and Eben 1973b Nomiyama and Nomiyama 1971). Testosterone has been implicated as a factor in the lower absorption of trichloroethylene in male rats compared with females (Kadry et al. 1991b McCormick and Abdel-Rahman 1991), and the same effect may occur in humans. 

Bimer G, Vamvakas S, Dekant W, et al. 1993. Nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-L-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans Implications for the risk of trichloroethene exposure. Environ Health Perspect 99 281-284. 

Dekant W, Metzler M, Henschler D. 1986a. Identification of S-l,2-dichlorovinyl- N-acetyl-cysteine as a urinary metabolite of trichloroethylene A possible explanation for its nephrocarcinogenicity in male rats. Biochem Pharmacol 35 2455-2458. 

It is known that nitrosamines with side-chains longer than methyl are metabolically hydroxylated on virtually every carbon. For example, the urinary metabolites in the rat of di-n-butylnitrosamine include the glucuronides of the following hydroxylated nitrosamines (42). 

Compound Species Dose (mg/kg) % of Dose CO2 (hr) Excreted Urine (hr) Urinary Metabolites (% of dose, hr) Reference... 

HydroxyNPYR [ ] has been identified as a urinary metabolite of NPYR in the rat (up to 1% of the dose), but was not detected when NPYR was incubated with subcellular fractions from rat liver and lung (13, 20). It has been proposed that further metabolism of leads to dimethy 1 amine, [ ], another urinary metabolite of NPYR, 2-Pyrrolidinone [3 ] has also been detected in the urine of rats treated with NPYR. Its origin has not been conclusively established, but it may form from pyrrol id inone-2-oxime (i6). 

In intact cell systems or vivo, the primary products of a-hydroxylation, 22. have not been detected. The principal urinary metabolites of NNN resulting from a-hydroxylation are keto acid 21 from 2 -hydroxyl at ion and hydroxy acid 21 from 5 -hydroxylation. Trace amounts of 7 y 21> H ve also been detected as urinary metabolites (34). The interrelationships of these metabolites as shown in Figure 2 have been confirmed by administration of each metabolite to F-344 rats (37). The other metabolites which are routinely observed in the urine are NNN-1-N-oxide U1 and 5-(3-pyridyl)-2-pyrrolidinone [norcotinine, ]. The p-hydroxy derivatives 2. 1 were also detected in the urine of NNN treated rats, but at less than 0.1% of the dose (36). An HPLC trace of the urinary metabolites of NNN is shown in Figure 3. Urine is the major route of excretion (80-90% of the dose) of NNN and its metabolites in the F-344 rat in contrast to NPYR which appears primarily as CO2 (70%) after a dose of 16 mg/kg (17). This is because the major urinary metabolite of NNN, hydroxy acid 21> fs not metabolized further, in contrast to 4-hy-droxybutyric acid [2, Figure 1] which is converted to CO2. In addition, a significant portion of NNN is excreted as NNN-l-N-oxide U ], a pathway not open to NPYR. 

The effects of deuterium substitution on the rates of a-hydroxylation of NNN have been measured. The results obtained in vitro, with rat liver microsomes, showed only a small deuterium isotope effect of 1.2 for 2 -hydroxylation, whereas a significant effect of 2.4-2.7 was observed for 5 -hydroxylation (33). Analogous results were obtained 2n vivo when the urinary metabolites... 

Figure 3. High pressure liquid chromatographic analysis of the urinary metabolites of 2 C N nitrosonornicotine in the rat after a dose of 300 mg/kg (31), Peaks...

Metabolism of NHEX- C in the rat results in dose dependent formation of C02> with 45% exhaled after a dose of 8 mg/kg NHEX but only 4% after 576 mg/kg (17). Similar results were obtained for NPYR and nitrosoheptamethyleneimine. At doses of 8-12 mg/kg NHEX, 33-37% of the radioactivity was excreted in the urine (17, 52). Urinary metabolites of NHEX were e-caprolactam, e-amino-caproic acid, and 6-aminocaprohydroxamic acid (52). The formation of 6-caprolactam is analogous to results with NPYR and NNN, in which 2-pyrrolidinone and norcotinine were observed as urinary metabolites. Caprolactam did not originate from hexamethylene-imine, a product of denitrosation. 

The metabolism of NMOR in the rat is outlined in Figure 4. o-Hydroxylation yields the unstable intermediates and the latter hydrolyzes to (2-hydroxyethoxy)acetaldehyde [7] which has been identified as a liver microsomal metabolite by isolation of the corresponding 2,4-dinitrophenylhydrazone (59). (2-Hydroxy-ethoxy)acetaldehyde, which exists predominantly as the cyclic hemiacetal was not detected in the urine of rats gavaged with 125 mg/kg NMOR. However, (2-hydroxyethoxy)acetic acid was a major urinary metabolite (16% of the dose). These transformations are analogous to those observed with NPYR and NNN. 

Figure 5. Gas-liquid chromatograms of the silylated urinary metabolites of Fl-nitrosomorpholine arul 3,3,5,5-tetradeutero- -nitrosomorpholine in the rat (59).

Szirmai M (1995) Total synthesis and analysis of major human urinary metabolites of dl-tetrahydrocannabinol, the principal psychoactive component of Cannabis sativa L. Dissertation, Uppsala University, Sweden... 

Tokunaga R, Takahata S, Onoda M, Ishi-i T, Sato K (1974) Evaluation of the exposure to organic solvent mixture. Comparative studies on detection tube and gas-liquid chromatographic methods, personal and stationary sampling, and urinary metabolite determination. Internationales Archiv Arbeitsmedizin 33 257-267. 

Fitzgerald, R. Blanke, R.V. Namsimhachari, N. Glennon, R.A. and Rosecrans, J.A. Identification of 3,4-methylenedioxyamphetamine (MDA) as a major urinary metabolite of 3,4-methylenedioxymeth-amphetamine (MDMA). Presented at the Committee on Problems of Drug Dependence Meeting, Philadelphia, PA, June 1987. 

Applicators, mixers, loaders, and others who mix, spray, or apply pesticides to crops face potential dermal and/or inhalation exposure when handling bulk quantities of the formulated active ingredients. Although the exposure periods are short and occur only a few times annually, an estimate of this exposure can be obtained by quantifying the excreted polar urinary metabolites. Atrazine is the most studied triazine for potential human exposure purposes, and, therefore, most of the reported methods address the determination of atrazine or atrazine and its metabolites in urine. To a lesser extent, methods are also reported for the analysis of atrazine in blood plasma and serum. 

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