Metabolites Indicator

Wilson MS, EL Madsen (1996) Field extraction of a transient intermediary metabolite indicative of real time in situ naphthalene biodegradation. Environ Sci Technol 30 2099-2103. 

In each of the profiles presented, several internal standards (20) are present and used for quantification. Increases or decreases in the relative concentration of these metabolites indicate disease and as such a positive screen. The complexity of the assay actually resides in the interpretation, which is illustrated in the flow chart shown in Fig. 14.3. 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

F (increased excretion of metabolites indicative of lipid peroxidation)... 

In animals, absorption of 3,3 -dichlorobenzidine from the gastrointestinal tract is rapid. Following a dose of 40 mg/kg, the plasma level of imchanged 3,3 -dichlorobenzidine attained a peak concentration of 1.25 g/mL at 4 hours in Sprague Dawley rats. Further, about 90% of the administered radioactivity was excreted in feces (via bile) and urine within 72 hours largely as metabolites, indicating a high bioavailability, typical of primary aiylamines. The elimination is biphasic, with half-lives of 6 hours and 14 hours in plasma for the rapid and slow phases, respectively (Hsu and Sikka 1982). 

A similar compound, bripiodionen (20), has been isolated from a Streptomyces sp [41], NMR spectral data determined for a fresh sample of the metabolite indicated predominantly a single isomer, probably that with 5(7 -configuration. If a MeOH or DMSO solution was left for a few days, a 1 1 mixture of two isomers (20,21) became evident, as found... 

Following oral treatment, suxibuzone is slowly absorbed from the gastrointestinal tract, but is very rapidly distributed in the body. In all species, suxibuzone was rapidly metabolized to phenylbutazone, which subsequently was metabolized to oxyphenbutazone and -hydroxyphenylbutazone. Animals treated with suxibuzone exhibited lower plasma concentrations of the parent drug than the phenylbutazone metabolite. Available data on phenylbutazone, the principal suxibuzone metabolite, indicated that phenylbutazone has carcinogenic potential for animals. 

Meyer, M.T. (1994). Geochemistry of cyanazine and its metabolites Indicators of contaminant transport in surface water of the midwest-ern US. Ph.D. Thesis, University of Kansas, Department of Geology. 

For example, full-scan mass spectra of buspirone contain an abundant [M+H]+ ion signal with little detectable fragmentation. The product ion spectrum reveals product ions and neutral losses associated with diagnostic substructures of buspirone (Figure 6.25). The product ion at mlz 122, for example, is indicative of the pyrimidine substructure. The presence of this ion in the product ion spectrum of a metabolite indicates a structure that contains the pyrimidine substructure. Similarly, the mlz 180 product ion is diagnostic of the azaspirone decane substructure, and the neutral loss of 164 (producing the mlz 222 product ion) is diagnostic of the butyl azaspirone decane dione substructure. 

Measurement of DEHP excretory metabolites indicate that about 11-15% of a 30 mg oral dose is excreted in human urine and, therefore, was absorbed (Schmid and Schlatter 1985). However, the total absorption is probably higher (perhaps 20-25%), since animal studies indicate that biliary excretion accounts for 15-20% of the absorbed dose (see Section 3.4.4.3). 

In the rat studies a major additional metabolic pathway was discovered, which had not been found in soils, i.e. the hydroxylation of the intact diflubenzuron molecule leading to the three different metabolites indicated in the Figure, which were found partly as conjugates. These hydroxy derivatives accounted for almost all the metabolites in the bile and for about half the metabolites in the urine. The rat metabolism studies will be published more extensively elsewhere (22.) ... 

Plants. Limited metabolism in most plant species minor metabolites indicate a pathway involving hydroxylation or oxidative loss of the tert-butyl group, followed by opening of the heterocyclic ring... 

Using brackets around the name of a metabolite indicates that the "concentration of the metabolite" is meant. 

Year of introduction Drug Commercialized as (m = microbial metabolite,) p = plant metabolite Indication Company... 

The alteration within the group of bound DDT-metabolites indicates either a different degradation pathway of incorporated DDT or the selective association of individual metabolites due to their different molecular structures. The significantly higher concentration of the DDT-related compounds as compared to unaltered bound contaminants suggests an enhanced incorporation of DDT or of its metabolites. 

The few direct toxicity comparisons using nitro-substituted phenols and their reduced metabolites indicate that the relationship between reduction of nitro to amino groups, and toxicity varies with the degree of nitration of the parent compound and the test species. The reduction of picric acid to picramic acid (2-A-4,6-DNP) and of 4-NP to 4-AP promoted an order of magnitude toxicity increase in lethal and sub-lethal assessments with several marine and freshwater invertebrates, fish, and algae [12,29,59] (Table 4.5). The reduction of 2,4-DNP to 4-A-2-NP, however, decreased toxicity to P. promelas by 2.5-fold [50,61],... 

As can be seen from the data, the thiol isomer (56) is a very strong poison for warm-blooded animals. However, it is rapidly excreted mostly in the form of its nontoxic metabolites. Following oral administration, the feces contain scarcely any metabolites, indicating that it is almost completely resorbed from the gastrointestinal tract. 

Chlorflavonin (166) was discovered in the culture broth of Aspergillus candidus [199-201]. A biosynthetic study of this fungal metabolite indicates that it is a true metabolite and is synthesized de novo by this microbe [202]. It was also detected in Aspergillus candidus and A. campestris [203]. The fungus Monilinia fructicola produces chloromonilinic acids A (167) and B (168) derived from chloromonilicin [204], to be discussed later. 

The most commonly reported nitroimidazoles in the literature include dimetridazole (DMZ), metronidazole (MNZ), ronidazole (RNZ), and ipronidazole (IPZ) (Fig. 7.7). More recently, additional members of this class such as carnidazole (CNZ), ornidazole (ONZ), tinidazole (TNZ), and ternidazole (TRZ) have also been incorporated into analytical methods. Extensive studies on the metabolism of nitroimidazoles in poultry, beef, swine, and fish have shown that the hydroxy metabolites of the parent compounds, formed by oxidation of the side-chain in the C2 position of the imidazole ring, are of additional concern. These compounds have been shown to have toxicity equal to that of their parent forms and are often rapidly formed by metabolism within the animal. Studies in both poultry and rainbow trout have shown that the distribution of parents to metabolites is analyte- and species-specific. As a result, it has been suggested that it is imperative that a residue control program considers both the parent and the metabolites. The metabolites indicated in the literature include MNZ-OH, IPZ-OH, and HMMNI (2-hydroxymethyl-l-methyl-5-nitroimidazole) as the hydroxy metabolites of MNZ, IPZ, and DMZ, respectively. HMMNI has also been identified as a metabolite of RNZ, but through a different pathway. HMMNI is not a major metabolite of RNZ, however, and is therefore not suitable on its own for use as a marker of RNZ use. 

Bauer and Abdalla (2001) proposed an alternative hypothesis to explain the apparent male awareness within a short period of an upcoming female parturial molt in aggregating species. Females of such species are actually hiding their reproductive condition until the molt to prevent harassment from males. Males simply may be sensing a female metabolite, indicating her reproductive state that she can no longer control as the actual molt approaches. 

Administer fomepizole (see p 448) or ethanoi (p 444) to saturate the enzyme alcohol dehydrogenase and prevent metabolism of ethylene glycol to its toxic metabolites. Indications for therapy include the following ... 

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