Modeling metabolites

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

Fig. 1 Dependence of extraction of chlorpromazine and three of its model metabolites into heptane containing 1.5% isoamyl alcohol on pH. The graph shows the percentage remaining in the aqueous solutions when equilibrated with equal volumes of the solvent mixture. (From Ref. l)...

The assignment of the Xj were made from an analysis of the AE values given in Table 3 for the model metabolites. 

Heflich, R.H. and Neft, R.E. (1994) Genetic toxicity of 2-acetylaminofluorene, 2-aminofluorene and some of their metabolites and model metabolites. Mutat. Res., 318, 73-114. 

The full extent of the toxicity of pesticides to aquatic life is not known. Although chronic toxicity testing is required for new substances, little is known about the long-term effects of older pesticides. Also, very little is known about the toxicity and occurrence of the products formed when pesticides break down (metabolites) or the many non-pesticidal additives (co-formulants and adjuvants) used in pesticide formulations. However, the future is looking brighter. New modelling techniques, EQS development, and the involvement of the NRA in the pesticide registration process, coupled with the development of newer, less persistent pesticides with lower dose rates, all should help to reduce the risk of pesticide pollution. 

The greater intensity of the band of the metabolite at 220 mis probably due to the presence of a second, superimposed chromophore which could also account for the shift of the minimum. On the other hand, the band near 300 m/u. has the expected intensity. Its broadness and displacement towards longer wavelength are probably due to the presence of a substituent on the double bond or benzenoid ring. That the assignment to a coumaroyl chromophore is essentially correct is evidenced by the fact that both M and the model compound underwent the same type of reaction on irradiation in the near-ultraviolet (Figure 4). The observed isosbestic points imply that the photoreaction is a simple one, such as A -> B or A = B, and is obviously the well-known light-induced trans- to c/r-isomerization (7) of cinnamic acid derivatives. 

Kielbasa W, Fung HL Pharmacokinetics of a model organic nitrite inhalant and its alcohol metabolite in rats. Drug Metab Dispos 28 386-391, 2000... 

A second kind of model is briefly treated, based on isotopic mass balance arguments, and it is shown that large isotopic discrimination during methano-genesis in ruminants may account for data trends when comparing herbivores and carnivores. A third class of model is sketched at the level of biochemical flows, where some fundamental points are made concerning points where the isotopic composition of metabolites may be altered. The relevance of this to nitrogen isotopic enrichment is considered. 

Here the effects of any one fractionating step can be expressed in a change in isotopic composition in a wider range of body tissue components, including the product as well as the precursor of a (reversible) reaction. The details depend on the explicit model, for example how rates depend on metabolite concentrations. Therefore, where a metabolic pathway is, or becomes, reversible, the effect on isofractionation on measured body components can be more widespread. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent chemical or metabolite in an animal system. There are two types of pharmacokinetic models data-based and physiologically-based. A data-based model divides the animal system into a series of compartments which, in general, do not represent real, identifiable anatomic regions of the body whereby the physiologically-based model compartments represent real anatomic regions of the body. 

No data were located concerning whether pharmacokinetics of endosulfan in children are different from adults. There are no adequate data to determine whether endosulfan or its metabolites can cross the placenta. Studies in animals addressing these issues would provide valuable information. Although endosulfan has been detected in human milk (Lutter et al. 1998), studies in animals showed very little accumulation of endosulfan residues in breast milk (Gorbach et al. 1968 Indraningsih et al. 1993), which is consistent with the rapid elimination of endosulfan from tissues and subsequent excretion via feces and urine. There are no PBPK models for endosulfan in either adults or children. There is no information to evaluate whether absorption, distribution, metabolism, or excretion of endosulfan in children is different than in adults. 

MetaDrug Metabolism database. Metabolite prediction. Metabolite prioritization, QSAR models for enzymes, transporters and network building algorithms for Systems-ADME/Tox www.genego.com... 

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