Metabolites primary

Neither the mechanism by which benzene damages bone marrow nor its role in the leukemia process are well understood. It is generally beheved that the toxic factor(s) is a metaboHte of benzene (107). Benzene is oxidized in the fiver to phenol [108-95-2] as the primary metabolite with hydroquinone [123-31-9] catechol [120-80-9] muconic acid [505-70-4] and 1,2,4-trihydroxybenzene [533-73-3] as significant secondary metabolites (108). Although the identity of the actual toxic metabolite or combination of metabolites responsible for the hematological abnormalities is not known, evidence suggests that benzene oxide, hydroquinone, benzoquinone, or muconic acid derivatives are possibly the ultimate carcinogenic species (96,103,107—112). 

Procainamide may be adininistered by iv, intramuscular (im), or po routes. After po dosing, 75—90% of the dmg is absorbed from the GI tract. About 25% of the amount absorbed undergoes first-pass metaboHsm in the fiver. The primary metabolite is A/-acetylprocainamide (NAPA) which has almost the same antiarrhythmic activity as procainamide. This is significant because the plasma concentration of NAPA relative to that of procainamide is 0.5—2.5. In terms of dmg metabolism there are two groups of patients those that rapidly acetylate and those that slowly acetylate procainamide. About 15—20% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 60—90 min. Therapeutic plasma concentrations are 4—10 lg/mL. Plasma half-lives of procainamide and NAPA, which are excreted mainly by the kidneys, are 2.5—4.5 and 6 h, respectively. About 50—60% is excreted as unchanged procainamide (1,2). 

Also the mirror image of the strueture I, eorreetly denoted as exo-3,10-dihydroxy-3,5,8,10-tetra-methyltrieyelo[6.2.2.0 ]dodeea-5,l 1-diene-4,9-dione, would be possible sinee enantiomers are not differentiated by NMR. A retro-Diels-Alder fragmentation of I to CsH/oO explains why the moleeular ion eorresponding to the moleeular formula C16//20O4 is not deteeted in the mass spee-trum. The metabolite I eould be formed by Diels-Alder dimerisation of 1,5-dimethyleyelohexa-l,3-dien-5-ol-6-one J as the primary metabolite which acts as diene and dienophile as well... 

All of the compounds we shall study in this Chapter are primary metabolites though both phases of growth will be studied. For example, as we shall see, citric add is produced continuously at low levels during trophophase but only accumulates at high concentration during idiophase. 

The growth of cells on a large scale is called industrial fermentation. Industrial fermentation is normally performed in a bioreactor, which controls aeration, pH and temperature. Microorganisms utilise an organic source and produce primary metabolites such as ethanol,... 

However, very recent studies by Fish and his co-workers (467) with butyltin compounds showed that the primary, metabolic reaction is not Sn-C bond-cleavage but carbon hydroxylation of the n-butyl group. Using [l- C]tetrabutyltin in an in vitro study, the major, primary metabolite was identified as a 2-hydroxybutyltributyltin derivative that underwent a rapid /3-elimination reaction to afford 1-butene and a tri-butyltin compound (467). 

Little is known regarding the pharmacokinetic properties of volatile nitrites in humans, particularly isobutyl nitrite and its primary metabolite, isobutyl alcohol. In rodents, after an intravenous infusion of isobutyl nitrite, blood concentrations peaked rapidly and then declined, with a half-life of 1.4 minutes and blood clearance rate of 2.9 L/min/kg (Kielbasa and Fung 2000). Approximately 98% of isobutyl nitrite is metabolized rapidly to isobutyl alcohol, concentrations of which also decline rapidly, with a half-life of 5.3 minutes. Bioavailability of inhaled isobutyl nitrite at a concentration of 300-900 ppm is estimated to be 43%. 

Equation (12.14) applies to all the elements that constitute a cell, but it is normally applied in the form of a carbon balance. The dominant terms in the balance are carbon in the cells, measured through Yxjs, and carbon in the primary metabolites—e.g., ethanol and CO2—measured through the Yp/s terms for these metabolites. 

The comparatively straightforward link between 5-HT and its primary metabolite, 5-HIAA, encouraged many researchers to use changes in the ratio of tissue concentrations of 5-HIAA and 5-HT as an index of the rate of release of 5-HT ex vivo. However, it has been clear for some time that the majority of 5-HT is metabolised in the cytoplasm by MAO before it is released from 5-HT nerve terminals. Consequently, the reliability of the 5-HIAA 5-HT ratio as an index of transmitter release is rather dubious, although it could be used as an acceptable measure of MAO activity. In any case, the development of in vivo microdialysis means that changes in the concentration of extracellular 5-HT can now be monitored directly which, under drug-free conditions, provides a far more reliable indication of any changes in the rate of release of 5-HT. 

Snznki H, Y Ohnishi, Y Fnrnsho, S Saknda, S Horinonchi (2006b) Novel benzene ring biosynthesis from C3 and C4 primary metabolites by two enzymes. J Biol Chem 281 36944-36951. 

However, there is no general requirement that enforcement methods need to monitor all metabolites of an active ingredient. The primary purpose of enforcement methods is to detect violations of good agricultural practice. For this purpose, residue levels found in samples from the market (so-called Market Basket Surveys) have to be compared with MRLs, which are derived from residue concentrations found in supervised trials. It is not necessary for this comparison to be based on the total pesticide residue. Most often the choice of a single compound (e.g., parent or primary metabolite) as a marker of the total pesticide residue is more feasible. Method development and the later method application are much easier in that case. Only for intake calculation purposes, e.g., when the daily intake of pesticide residues (calculated from the results... 

In subsequent smdies, it was shown that, atfer hydrolysis, about 42% of the total radioactive residue in grain may be identified as 4-fert-butylcyclohexanone. Moreover, 34-90% of the TRR was extracted by heating the plant material under reflux with a mixture of methanol and hydrochloric acid. The performance of that method was properly demonstrated by individual fortification experiments with the parent compound and the three primary metabolites (bold in Figure 1). 

On the other hand, some sensible reduction may be acceptable. In the spiroxamine example, an appropriate reduced validation protocol may be as follows a full set of recovery experiments at both levels performed with the intact spiroxamine (which has the longest reaction pathway to the common moiety) and separately with one primary metabolite. Such two complete validations should be an acceptable test of the working range of the common moiety method. 

With the help of fortifications at the LOQ, method sensitivity can be demonstrated for the remaining primary metabolites. 

Reguiatory position The residue definition includes terbacil and its three primary metabolites. Metabolite A, Metabolite B and Metabolite C... 

An example of an LC/MS/MS method with an LOQ of 0.01 mg kg is illustrated in Figure 9. This method was used to analyze tepraloxydim and its primary metabolite... 

Regulatory position The residue definition is for both imibenconazole and its primary metabolite (imibenconazole-debenzyl)... 

Plant samples are homogenized with sodium hydrogencarbonate aqueous solution to prevent decomposition of the analytes during homogenization. Imibenconazole and its primary metabolite, imibenconazole-debenzyl, are extracted from plan materials and soil with methanol. After evaporation of methanol from the extracts, the residues are extracted with dichloromethane from the residual aqueous solution. The dichloromethane phase is cleaned up on Florisil and Cig columns. Imibenconazole and imibenconazole-debenzyl are determined by gas chromatography/nitrogen-phosphorus detection (GC/NPD). 

The Ames test involves the reversion from a his— to his+ phenotype in any one of multiple bacterial strains (usually five strains are tested simultaneously). If the addition of test compound to a his— strain of bacteria allows them to grow on histidine deficient media, the obvious conclusion is compound-induced mutagenesis and a high potential hazard for the compound being carcinogenic. This test can also be conducted in the presence or absence of metabolic activation, in order to provide more information on potential risks (i.e., the parent compound may not be mutagenic, but the primary metabolite may present a safety risk). In practice, a positive Ames test almost always leads to discontinuing work on a compound of interest, and so these data are always collected prior to nomination of a compound for development. 

A sex difference in the rate of conversion of DIMP to its primary metabolite was observed after intravenous administration of 14C-DIMP in rats (Bucci et al. 1992). The males appeared to convert DIMP to IMPA more actively than the females. The apparent plasma elimination half-life of DIMP was about 45 minutes in males and up to 250 minutes in females. Both the rate and total excretion of the administered dose in urine were also higher in male rats. However, this sex difference was not observed for orally-administered DIMP in minks (Bucci et al. 1992 Weiss et al. 1994). 

Exposure. No biomarkers of exposure were identified that were specific to diisopropyl methylphosphonate. Although standard procedures exist for identifying diisopropyl methylphosphonate s primary metabolite (IMP A) in plasma, urine, and feces (Weiss et al. 1994), the detection of IMP A is not unique to diisopropyl methylphosphonate exposure. IMPA is also a major metabolite of GB (Sarin) (Little et al. 1986). In addition, IMPA is cleared from the body rapidly, making it a useful indicator for recent exposure only. 

Mash D., Staley J., Baumann M., Rothman R., Hearn W. Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Life Sci. 57 PL45, 1995. 

Staley J., Ouyang Q., Pablo J. et al. Pharmacological screen for activities of 12-hydroxyibogamine a primary metabolite of the indole alkaloid ibogaine. Psychopharmacology. 127 10, 1996. 

The answer is c. (Hardman, pp 649—650.) Acute hyperuricemia, which often occurs in patients who are treated with cytotoxic drugs for neoplasic disorders, can lead to the deposition of urate crystals in the kidneys and their collecting ducts. This can produce partial or complete obstruction of the collecting ducts, renal pelvis, or ureter. Allopurinol and its primary metabolite, alloxanthine, are inhibitors of xanthine oxidase, an enzyme that catalyzes the oxidation of hypo xanthine and xanthine to uric acid. The use of allopurinol in patients at risk can markedly reduce the likelihood that they will develop acute uric acid nephropathy. 

Aniline is rapidly and extensively metabolized following oral administration. In the pig and sheep, approximately 30% of a 50-mg/kg dose of 14C-labeled aniline was excreted in the urine, as measured by 14C activity, within 3 h after administration, whereas approximately 50% of the dose was excreted in rats. Within 24 h, more than half the administered dose was excreted by pigs and sheep and 96% of the dose was excreted by rats. Fecal radioactivity was low. A-acetylated metabolites accounted for most of the excretion—/V-acetyl-/>-aminophenyl glucuronide being the primary metabolite in sheep and pig urine and /V-acetyl-/>-aminophenyl sulfate being the primary metabolite in the rat (Kao et al. 1978). Biologic monitoring of workers exposed to aniline showed that /i-aminophenol constituted 15-55% of the parent compound in the urine the o- and ra-isomers were also formed (Piotrowski 1984). 

Giardi, M.T., M.C. Giardina, and G. Filacchioni. 1985. Chemical and biological degradation of primary metabolites of atrazine by tiNocardia strain. Agric. Biol. Chem. 49 1551-1558. 

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