Metabolite stability

Coutts RT, Su P, Baker GB, Daneshtalab M. 1993. Metabolism of imipramine in vitro by isozyme CYP2D6 expressed in a human cell line, and observations on metabolite stability. J Chromatogr B Biomed Appl 615 265. 

First-pass clearance can be tracked to gut-stability or metabolism by phase I and then either direct clearance or clearance of the metabolite by phase It enzymes or biliary, renal or plasma clearance. Metabolite stability by phase I enzymes include inhibition, induction, regiospecificity, lability or affinity toward several cytochrome... 

Payne (2004) Pitfalls in the measurement of some intermediary metabolites stabilization of lactate and pyruvate. Ann Clin Biochem 41 83... 

The effects of storage of a known concentrate of PNP under different degrees of temperature and with different preservatives added are shown in Table I. With formaldehyde added at room temperature the specimen degraded from 2.4 to 2.2 p.p.m. of PNP in 5 days, a decline that would not have seriously influenced the conclusions drawn in a surveillance program. This metabolite stability was subsequently confirmed in other urine samples. 

Figure 10.11 Results for adatanserin of (a) a microsomal metabolite stability study, and (b) the metabolite profiling study performed after 10 min incubation. Metabolites Ml and M2 are dihydroxy-analogues, M3, M4, M5, and M9 are hydroxy-analogues, and M6, M7, and M8 still have to be identified. Reprinted from [76] with permission. 2001, John Wiley Sons, Ltd.

The most frequent of the domain structures are the alpha/beta (a/P) domains, which consist of a central parallel or mixed P sheet surrounded by a helices. All the glycolytic enzymes are a/p structures as are many other enzymes as well as proteins that bind and transport metabolites. In a/p domains, binding crevices are formed by loop regions. These regions do not contribute to the structural stability of the fold but participate in binding and catalytic action. 

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

While recent attention has been largely on proteins, it should be borne in mind that membrane fusion ultimately involves the merger of phospholipid bilayers. However, little is known about the specific membrane lipid requirements. When membranes fuse, energetically unfavorable transition states are generated that may require specific lipids and lipid domains for stabilization. Although there is some evidence for a specific influence of lipids on exocytosis, it is still unclear whether specific lipid metabolites are needed or even generated at the site of membrane merger. 

Solanesol and other prenyl alcohols are important as metabolites in mulberry and tobacco leaves and in the synthesis of isoprenoid quinones. Hence, Sato and collaborators107 have developed a stereoselective synthesis of all-trans-polyprenol alcohols up to C50. Construction of the requisite skeletons was accomplished by the alkylation of a p-toluenesulphonyl-stabilized carbanion, followed by reductive desulphonylation of the resulting allylic sulphonyl group. This was achieved most efficiently by the use of a large excess of lithium metal in ethylamine (equation (43)), although all reaction conditions led to mixtures. The minor product results from double bond rearrangement. 

The novel marine natural product laulimalide (65), a metabolite of various sponges, has received attention as a potential antitumor agent due to its taxol-like ability to stabilize microtubules. There has been considerable synthetic effort toward 65, culminating within not more than 2 years in as many as ten... 

Kojic acid is a fungal metabolite (5-hydroxy-4 pyran 4-1-2 methyl) known to inhibit tyrosinase and used to treat melasma at concentration of 2-4% twice a day. The stability is one of its advantages if compared with hydroquinone. Unfortunately, it is considered to have a high sensitizing potential. 

Stabilizers used were oxiranes (1,2-epoxybutane and epiehlorohydrin). Results not statistically compared with others in the study Testing effects of chloral, a metabolite of trichloroethylene... 

Some metabolites of curcumin (particularly tetrahydrocurcumin) may also participate in producing the observed effects of curcumin in different models because these metabolites display greater stabilities than the parent curcumin molecule at physiological pH. Recent data show similar modes of action of curcumin metabolites regarding antioxidant enzyme induction and inhibition of multidrug-resistant proteins. " Additional data indicate that curcumin may even act against other types of diseases such as atherosclerosis " " and Alzheimer s disease. " - " ... 

Schldmann M, P Fischer, E Schmidt, H-J Knackmuss (1990b) Enzymatic formation, stability, and spontaneous reactions of 4-fluoromuconolactone, a metabolite of the bacterial degradation of 4-fluorobenzoate. J Bacterial 172 5119-5129. 

Bressler DC, PM Fedorak (2001a) Purification, stability, and mineralization of 3-hydroxy-2-formylbenzothio-phene, a metabolite of dibenzothiophene. Appl Environ Microbiol 67 821-826. 

Data on the existence and stability of metabolites and their toxicity to other biota... 

The collected plant samples are analyzed as soon as possible after harvest. When samples or their extracts need to be stored, appropriate storage conditions are imperative. The stability of metabolites should be monitored during the storage period. 

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