Metabolite toxic potential

The analyst should also be alert to the fact that some drug residues become bound to the tissues of the animal and that this may have the effect of deactivating the toxic potential of the residue. However, determining the total concentration of the parent compound and/or its major metabolites generally ensures the greatest margin of safety. 

Some explanations of the lower risk of agranulocytosis have been advanced after an in vitro cytotoxicity study (209). Like clozapine, olanzapine is oxidized to a reactive nitrenium ion by HOC1, the major oxidant produced in activated neutrophils. However, the olanzapine-reactive metabolite has a lower propensity to cause toxicity to human neutrophils, monocytes, and HL-60 cells than the reactive clozapine nitrenium ion. The lower toxic potential of the olanzapine reactive metabolite, in conjunction with the lower therapeutic plasma concentrations of olanzapine compared with clozapine, may help to explain this difference between the drugs. 

Modem inhalation anesthetics are fluoiinated to reduce flammabihty. Initially, these inhaled agents were believed to be biochemically inert. Over the past 30 years, however, research findings have demonstrated that not only are inhaled anesthetics metabolized in vivo [27], but their metabolites are also responsible for both acute and chronic toxicities [28,29]. Therefore, the use of some anesthetics has been discontinued, including methoxyflurane because of its nephrotoxicity and other anesthetics are more selectively used, e.g. halothane due to a rare incidence of liver toxicity. Studies have also provided the impetus to develop new agents - isoflurane and desflurane - with properties that lower their toxic potential. The result has been improved safety, but there is room for further improvement as our insight into toxicological mechanisms expands. 

ARE REACTIVE METABOLITE TRAPPING AND COVALENT BINDING STUDIES RELIABLE PREDICTORS OF TOXICITY POTENTIAL OF DRUG CANDIDATES ... 

BRN modeling is performed using a simulation tool called BioTRaNS (Biochemical Tool for Reaction Network 5imulation). Once validated with experimental data, this methodology can predict and simulate in a quantitative and time-dependent manner the formation and disappearance of all metabolites, including potentially toxic reactive intermediates, such as... 

The extreme toxic potential of marine metabolites often prevents their application in medicine. However, a number of metabolites proved to be valuable tools in biochemistry, cell and molecular biology. For instance the neurotoxic maitotoxin [109-112] (interaction with extracellular calcium enhancement of calcium influx [113]), the neurotoxic brevetoxin B [114] (interaction with the binding-site-5 of voltage-sensitive sodium channels [115]), tetrodotoxin and saxitoxin (voltage clamp analysis to study sodium channels and excitatory phenomena [116] tetrodotoxin abolishes brevetoxin B activity [117]), okadaic acid [118-120] (analysis of phosphorylation and dephosphorylation processes in eukaryotic cell metabolism [121]), and palytoxin (stimulation of arachidonic acid metabolism synergistically with TPA-type promoters [122]). 

Metabolism of a chemical plays an essential role in the toxicity evaluation of a chemical. It will usually result in the conversion to a more water-soluble metabolite, enhancing the excretion ratio and shortening the half-life of the chemical in vitro. However, biotransformation may also result in a metabolite with a higher reactivity, thus increasing the toxic potential of exposure to the chemical. Because in many cases in vitro systems do not account for this bioactivation, this factor is considered an important drawback of in vitro toxicity determinations [18]. 

Leung et al. 1988). However, these studies are limited to the biotransformation of individual compounds. Since most metabolic pathways have been identified or can be predicted for the individual PAHs. it is now important to understand how these metabolic pathways are affected when the PAHs compete. The carcinogenic and toxic potential of PAHs is associated with their metabolites. Alterations in rates of metabolism and metabolite profiles may affect the toxic consequences of PAHs. 

The differentiation of the toxic potentials of parent compounds from those of chemically stable metabolites is relatively simple. When a response depends on the reversible binding of the drug or metabolite to receptor sites and appears soon after the administration of drug, the intensity and duration of the response frequently depends on the drug concentration in blood. Studying the relationship between the duration of action of a drug and the concentration in blood, however, will fail when the response is caused in part by a metabo-... 

These strategies will fail, however, when the toxicity is caused by short-lived chemically reactive metabolites. Such metabolites are not easily isolated and thus their identity must be inferred from indirect evidence based on their ultimate decomposition products. Even if the chemically reactive metabolites were identified they would not be easily synthesized or purified. Moreover, their toxic potential is not easily studied because they would be inactivated during their passage from the sites of administration to their target organs. Clearly a different strategy must be employed to determine which chemically reactive metabolites are toxic and which are innocuous. 

TPmixture Toxic potential of the mixture of parent compound and its metabolites... 

For assessing the risk from transformation products in the second and third case, one must, on the one hand, know which quantity of each of the different transformation products is present in the environment. On the other hand, one needs to know the toxic potential relative to the parent compound. Herein, we describe a simple prediction model for simulating the effects of mixtures of parent compounds and their transformation products. The model was developed for metabolites of human pharmaceuticals [11,12] and will... 

The model for predicting the ecotoxicological effects of mixtures of metabolites and their parent compounds assumes concentration addition of the effects of metabolites and their parent compound. If concentration addition holds and additionally all assumptions pertinent to the toxic equivalency concept apply [14], the toxic potential of the mixture of a parent compound and its metabolites, TPmixture. is defined as the sum of the fraction of parent after metabolism, /parent, and the product of the fraction of each metabohte i, fi, scaled by the potency of the given metabolite RPi, in relation to 100% potency of the parent compound (Eq. 1). 

Fig. 2 a Case I Parent compound and metabolite are baseline toxicants. Note that, for consistency reasons, we used the computed ECSObaseiine, parent rather than the experimental value ECSOexperimentai,parent lo define RPbaseiine,/ lu this Way, TRpg ent i equal to 1 in all model calculations. The empty circles stand for estimated values, the filled circles for experimental data, b Case II Parent molecule is specifically toxic and there is no information on the mode of toxic action of the metabolite. Therefore, for metabolite i, a minimum RPmin,i> representing baseline toxicity, as well as a maximum RPmax, were computed. RPmax.i represents a metabolite that potentially exhibits the same specific mechanism as the parent compound. The empty circles stand for estimated values, the filled circles for experimental data, c Case III The specific toxicity of the metabolits is confirmed by experimental evidence. The RPspecific, of the metabolite is calculated directly from the experimental data. The empty circles stand for estimated values, the filled circles for experimental data... 

Note that the different metabolites i of a given parent compound do not necessarily all fall in the same category. While the toxic potential TP ixture can still be easily computed in such a case, error estimation becomes difficult due to varying degrees of uncertainty in the predictions for the different metabo-htes. 

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