Metabolites relative potency

The relative contribution of the active metabolites of the benzodiazepines to the overall therapeutic effect of the parent compound will depend on the concentration of the metabolite formed, its agonist potency at central benzodiazepine receptors and its lipophilicity. For example, after the chronic administration of diazepam, desmethyldiazepam accumulates in the brain. As this metabolite has potency at the benzodiazepine receptors equal to diazepam, the metabolite probably plays an important part in the overall action of diazepam. In the case of clobazam, however, even though the active metabolite desmethylclobazam is present in higher concentrations than the parent compound after chronic administration, it has a lower potency than clobazam and therefore is of less importance than the parent compound with regard to the anxiolytic effect. 

There are three aerosolized corticosteroid preparatioias available in MDI formulation for administration to horses via the Equine AeroMask beclometasone dipropionate, fluticasone propionate and flunisolide (Table 16.2). In terms of the relative potency, fluticasone is more potent than beclometasone, which is more potent than flunisolide, which is equipotent to triamcinolone. Using dexamethasone as the standard (1.0), the relative glucocorticoid receptor affinity of the common corticosteroids is flunisolide 1.9, triamcinolone 2.0, beclometasone (active metabolite) 13.5 and fluticasone propionate 22.0 (Barnes et al 1998). The pulmonary residence time of the aerosolized corticosteroids is determined by the lipophilicity of each drug. Flunisolide has intermediate water solubility (lOmg/ml), simitar to... 

Reinli and Block (1996) developed a compendium of literature values with 36 references for phytoestrogens (coumestrol, daidzein, genistein, biochanin A and formononetin) in foods. They also reported the relative potency of these phytoestrogen and equol (metabolites found in urine) in vitro and in vivo. Similar to the USDA-ISU database, this database reported total daidzein and genistein, which were estimated by the hydrolysis method or by normalizing the molecular weight differences of... 

ABSORPTION AND ELIMINATION The relative potency, oral bioavaUability, plasma tj, and route of elimination for amiloride and triamterene are hsted in Table 28-6. Amiloride is eliminated predominantly by urinary excretion of intact drug. Triamterene is metabolized extensively to an active metabolite, 4-hydroxytriamterene sulfate, and this metabolite is excreted in the urine. Therefore, the toxicity of triamterene may be enhanced in both hepatic disease (decreased metabolism of triamterene) and renal failure (decreased urinary excretion of active metabolite). 

RPj Relative potency of the given metabolite i, in relation to 100% potency... 

The fractions of each metabolite / can be derived from measured environmental concentrations, from knowledge about the metabolites formed and excreted by an organism (e.g. often available in the pharmaceutical Htera-ture), or from predictions generated using fate and exposure models (see Fenner et al., 2008, in this volume). Examples are given in the case studies below. The computation of the relative potency of a metabolite, RP,-, is central to the model and is derived in detail in the next section. 

If experimental data for the parent compound and the metabolites are available, the relative potency of a given metabolite i can be calculated according to Eq. 2... 

Fig.1 Flow-chart for model selection and models to derive the relative potency of the metabolites RP,- in relation to 100% potency of the parent compound...

The combination of the RP/ with - derived from the RAC given in Gasser et al. [41] yield the toxic potentials depicted in Fig. 7. The transformation product DBA is quantitatively significant, but, due to its low relative potency, it does not contribute much to the toxic potential of the mixture. The contribution of the quantitatively less prevalent metabolites DIA and HA is even lower. Consequently, the TPmixture is dominated by the parent compound. It can thus be concluded that, in the case of atrazine, the contribution of the transformation products to the total aquatic risk is negligible. 

Diclofenac is a nonsteroid anti-inflammatory drug. The main metabolites of diclofenac are the conjugates (here modeled as glucoronides) and 4 -hydroxypropranolol. Other oxidation products occur in traces only [58-60] (Figs. 15 and 16). All these metabolites are about a factor four less toxic than the parent compound, with the exception of the di-hydroxylated diclofenac, whose relative potency was modeled to be only 2% of the parent compound (Fig. 15). Since the parent compound was baseline toxic for all investigated ecotoxicity endpoints (Fig. 15) and for other acute endpoints [17], we also assumed that the metabolites were baseline toxicants. 

In accordance with their small relative potencies, the metabolites are predicted to not dominate the TPmixture (Fig- 16) and the TPmixture to be smaller than one, indicating that metabolism in the human body reduces the ecotoxicity of diclofenac. 

In vivo studies in animals suggest that endosulfan may disrupt normal reproductive hormone levels in male animals, but that it is not an endocrine disrupter in females. Persistent depressed testicular testosterone was seen in male rats after intermediate duration oral exposures to endosulfan. In ovariectomized female rats, orally administered endosulfan did not induce normal development of female reproductive tissues, and in female mice and immature female rats, acute parenteral exposure to endosulfan did not affect several endocrine-related end points. In vitro studies have evaluated endosulfan for estrogen receptor (ER) and cytosolic protein binding affinity, ER-mediated reporter gene expression, estrogenic induction of cell proliferation, and alteration of relative abundance of active estradiol metabolites. Overall, in vitro evidence in favor of endosulfan estrogenicity indicates relatively weak potency compared to 17[3-estradiol. Apparently contradictory results were reported in different... 

The developments which led to the present day concepts of the metabolic activation of hydrocarbons did not arise from the classical approach of identifying metabolites of greater biological potency than the parent compound, but from an approach dependent upon the assumption (or presumption) that the interaction of carcinogens with DNA is a key event in the initiation of the carcinogenic process. Brookes and Lawley (49) found in 1964 that when radioactive hydrocarbons are applied to the skin of mice, they become covalently bound to the DNA of the skin. Moreover, the extents of binding to DNA for various hydrocarbons followed fairly closely their relative carcinogenic activities. 

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