Metabolites in tissue

Exposure. Known biomarkers of exposure to endosulfan include the measurement of endosulfan or its metabolites in tissue and excreta (Deema et al. 1966 Dorough et al. 1978 Gorbach et al. 1968) these measurements can indicate whether absorption of endosulfan has occurred. The presence of the parent compound and its metabolites are specific biomarkers for endosulfan exposure. However, no studies are available that quantify the concentrations of endosulfan or its metabolites in relation to specific environmental exposure levels. Since endosulfan induces cytochrome P450-dependent monooxygenases... 

Agarwal et al. 1978), the quantification of these specific enzymes may indicate that exposure to endosulfan has occurred. Blood tests, such as decay curves for aminopyrine in plasma, which are semiquantitative indices of liver enzyme induction, have been used successfully in the past to demonstrate enzyme induction in pesticide-exposed workers. Because numerous chemicals found at hazardous waste sites also induce these hepatic enzymes, these measurements are not specific for endosulfan exposure. However, measurements of enzyme activity, together with the detection of the parent compound or its metabolites in tissue or excreta, can be useful indicators of exposure. All of these potential biomarkers require further verification in epidemiological studies. Further studies with focus on the development of methods to separate and measure the estrogenicity of endosulfan in in vitro assays would be valuable since these assays are more sensitive and discriminative than other conventional biomarkers. Preliminary results have been presented by Sonnenschein et al. (1995). 

Reviews on the fate of aromatic hydrocarbons in marine organisms have been published (2,3,4). They indicated that a substantial amount of information exists on the accumulation of these compounds in a variety of phylogenetically diverse organisms. Recently, emphasis has shifted toward studies of bioconversions of these hydrocarbons. Work has been conducted on enzymes mediating the degradation of aromatic hydrocarbons and on the formation and retention of metabolites. Identifications of individual metabolites in tissues and body fluids of several marine organisms exposed to radiolabeled aromatic hydrocarbons have been made however, insufficient information is available to determine the extent of differences in metabolite profiles as evinced from chromatographic data. 

Penicillins form several major metabolites which are excreted in the urine (83,84). These metabolites are usually inactive microbio-logically and they would not be detected by the usual microbiological tests. There are no analytical methods for these metabolites in tissues and, therefore, little is known as to their occurrence and persistence in tissues. There are no methods available for identifying residues of some commonly used B-lactam antibiotics including carbenicillin and ticarcillin. For cephapirin and ampicillin, except for one HPLC method for ampicillin in milk (79) only TLC procedures (72-74,76) with detection by bioautography are reported. 

Bechtold WE, Sabourin PJ, Henderson RF. 1988. Reverse isotope-dilution method for determining benzene and metabolites in tissues. J Anal Toxicol 12(4) 176-179. 

Bennett, R.N. et al., Profiling glucosinolates, flavonoids, alkaloids, and other secondary metabolites in tissues of Azima tetracantha L. (Salvadoraceae), J. Agric. Food Chem., 52, 5856, 2004. 

In the past decade, eight inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients (Table 5.1.1) [7, 9, 10]. Two of these disorders are due to a defect of the enzyme mevalonate kinase, and in principle affect the synthesis of all isoprenoids (Fig. 5.1.1) [5]. The hallmark of these two disorders is the accumulation of mevalonic acid in body fluids and tissues, which can be detected by organic acid analysis, or preferably, by stable-isotope dilution gas chromatography (GC)-mass spectrometry (GC-MS) [2]. Confirmative diagnostic possibilities include direct measurement of mevalonate kinase activities in white blood cells or primary skin fibroblasts [3] from patients, and/or molecular analysis of the MVK gene [8]. 

The effect of cooking on incurred residues of oxfendazole in cattle liver has been also investigated (88). However, the results drawn from this study are inconclusive due to several variable factors. One such factor is the unstable equilibrium between oxfendazole, oxfendazole sulfone, and fenbendazole in the incurred tissue. Other factor is the overall instability of oxfendazole and its metabolites in tissue during frozen storage. Another factor is the variable distribution of the residues within the tissue used for the study and the effect of protein binding on the extractability of the residues from the tissue. It was nevertheless... 

The rates of the various reactions will vary. This may be due to the availability of cofactors, concentration of enzyme in a particular tissue, competition with other, possibly endogenous, substrates or to intrinsic factors within the enzymes involved. This variation in rates will clearly affect the concentrations of metabolites in tissues, and the half-life of parent compound and metabolites. It may lead to accumulation of intermediate metabolites. 

The pharmacokinetics of NOR and its metabolites in tissue residues was also studied (205). Samples of fat, kidney, lung, and muscle were extracted in methylenechloride and sodium phosphate (pH 7.5). An HPLC with UV detector was used. Detection limits were 3 /ug/kg and 5 /zg/kg for NOR and its metabolites. 

As previously noted, there are no data available on the levels of BCME or its metabolites in tissues of humans or animals. Although there are a number of epidemiological studies involving occupational exposure to BCME, there are no data on the concentrations of BCME to which workers were exposed. Consequently, there is no information on the relationship between environmental levels of BCME and any health effect or tissue level in exposed humans. 

Cornett, D. S., Frappier, S. L., and Caprioli, R. M. (2008). Imaging drugs and metabolites in tissue using Fourier transform mass spectrometry. In Proceedings of the 56th ASMS Conference on Mass Spectrometry and Allied Topics. ASMS, Denver, CO. 

Cornett D, Frappier S, Caprioli R (2008) MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue. Anal Chem 80 5648-5653. doi 10.1021/ac800617s... 

Wiseman J, Ifa D, Zhu Y, Kissinger C, Manicke N, Kissinger P, Cooks R (2008) Desorption electrospray ionization mass spectrometry imaging drug and metabolites in tissues. Proc Natl Acad Sci USA 105(47) 18120-18125. doi 10.1073/pnas.0801066105... 

Nemes P, Barton A, Vertes A (2009) Three-dimensional imaging of metabolites in tissue under ambient conditions by laser ablation electrospray ionization mass spectrometry. Anal Chem 81 6668-6675. doi 10.1021/ac900745e... 

Most patients with biotinidase deficiency excrete large quantities of biocytin in their urine, but there has been no evidence of accumulation of this metabolite in tissues. It remains to be determined whether biotin therapy is harmful because it may increase the concentration of biocytin in these children. 

Pharmacokinetics describes the processes of the uptake of drugs by the body, the biotransformations they undergo, the distribution of the drugs and their metabolites in tissue, and the elimination of the drugs and their metabolites from the body. Clinical pharmacokinetics is the discipline that applies the principles of pharmacokinetics to safe and effective therapeutic management of an individual patient. It is this aspect of pharmacology that most strongly influences the interpretation of TDM results and that is dealt with in more detail in this chapter. 

The assessment of the distribution of a drug and its metabolites in tissues can be of high interest for the evaluation of its pharmaceutical properties (87). In comparison to traditional drug imaging modalities, such as autoradiography, MSI offers the label-free and simultaneous imaging of one or several drugs and their metabolites in tissue (23). In consequence, MSI has been rapidly... 

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). 

The measurement of the steroid hormones and their metabolites in tissues and body fluids has long been a major technical problem to endocrinologists and biochemists, and even more of a problem to clinical chemists. Steroid biochemistry has been somewhat esoteric and to some... 

Physiologically based pharmacokinetic (PB-PK) models for some JP-8 components have been developed to understand the relationship between vapor concentrations and accumulation in tissue and blood compartments. When appropriately developed and validated, PB-PK models can provide a time course of distribution of a chemical or its metabolites in tissues and show the effect of changingphysiologic characteristics on plasma and tissue concentrations. PB-PK models have been applied to predict toxicokinetic parameters and to scale dose in different species. 

Regarding the persistence of bound residues, as compared to the parent compound and other metabolites, and their high bioavailibility when fed to rats (63), special attention was paid to their identity and possible toxic properties. In particular the possible presence of reversible protein-bound metabolites in tissues of treated animals was hypothesized to imply a possible health-risk for the consumer (63). The issue of bound-residues of furazolidone and other drugs has long been one of the most controversial and difficult problems in the field of residue toxicology (64, 65). 

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