Biotransformation pathways, species

The species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance of esfenvalerate and deltamethrin using rat and human liver microsomes were examined [33]. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The CLint of esfenvalerate was estimated to be threefold greater in rodents than in humans on a per kg body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes however, in human liver microsomes, deltamethrin was eliminated almost entirely via... 

M. Comet, A. Callaerts, U. Jorritsma, H. Bolt, A. Vercruysse, V. Rogiers, Species-Dependent Differences in Biotransformation Pathways of 2-Methylpropene (Isobutene) , Chem. Res. Toxicol. 1995, 8, 987 - 992. 

Biotransformation pathways of nitroaromatic compounds are believed to result from nitroreductases that have the ability to use nitro as either one- or two-electron acceptors. One-electron acceptance by the nitro compounds results in the production of the nitro radical-anion. This nitro radical-anion becomes one of the most aggressive species in biological systems because of its reaction on endogenous molecules (DNA bases) and its well-known catalytic ability to transfer one electron to molecular oxygen with superoxide anion formation. 

Depending on the species, parbendazole, mebendazole, albendazole, oxfendazole, cambendazole, and febantel can be teratogenic in the parent form or indirectly from metabolite formation. Oxibendazole and fenbendazole in parent form are not teratogenic, although one of the metabolites of fenbendazole, a sulfoxide found in the milk of cows treated with fenbendazole, is teratogenic in the rat and sheep. Albendazole displays similar biotransformation pathways in cattle as it does in sheep, yet the bovine animal is refractory to its teratogenic effect at normal dosage rates. 

Where possible, an evaluation should use pharmacokinetic data, including metabolic and mechanism-of-action information, to determine the relevance of experimental data to humans. Should the available data for a particular species demonstrate a pharmacokinetic pattern similar to that found in humans, the data from that species will be considered relevant. But if, for example, an agent given to an experimental animal requires biotransformation to produce toxicity, and if humans are known to be incapable of that biotransformation pathway, then toxicity data from that experimental animal species would be considered irrelevant to humans. 

The absorption and metabolic profiles of antiobesity drugs and appetite stimulants in humans are described below. Several novel biotransformation pathways in rodent species... 

A schematic representation of the possible molecular fate and effects of organic xenobiotics taken up into animals is given in Fig. 1. It shows the relationship between the biotransformation pathways involved in the detoxication and removal of xenobiotics and those involved in the generation of toxic molecular species. It identifies four potential sources of toxic molecular species derived either directly or indirectly from the presence of the organic xenobiotic, viz. the parent compound itself, reactive metabolites and free radical derivatives of the compound, and enhanced production of toxic oxygen species (oxyradicals). The scheme and the details of the reactions and enzymes involved (Table 1-3) are based largely on mammalian and other vertebrate studies. 

AP -DDT is rather stable biochemically as well as chemically. Thus, it is markedly persistent in many species on account of its slow biotransformation. Metabolism of p,p -DDT is complex, and there is still some controversy about its specifics. The most important metabolic pathways are shown in Figure 5.2. 

NADPH-independent hydrolytic metabolism. The CLint for deltamethrin was estimated to be twice as rapid in humans as in rats on a per kg body weight basis. Metabolism by purified rat and human CESs was used to examine further the species differences in hydrolysis of deltamethrin and esfenvalerate. Results of CES metabolism revealed that hCEl was markedly more active toward deltamethrin than the Class I rat CESs, hydrolase A and B, and the Class II human CES, hCE2 however, hydrolase A metabolized esfenvalerate twice as fast as hCEl, whereas hydrolase B and hCEl hydrolyzed esfenvalerate at equal rates. These studies demonstrated a significant species difference in the in vitro pathways of biotransformation of deltamethrin in rat and human liver microsomes, which was due in part to differences in the intrinsic activities of rat and human CESs. 

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