Biotransformation pathways, species differences

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... 

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. 

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. 

Karim et al determined that the main pathway of disopyramide metabolism involved N-dealky-lation of the isopropyl group and arylhydroxy-lation, with a marked species difference in biotransformation between dog, rat, and man. 

Species variation has been observed in many oxidative biotransformation reactions. For example, metabolism of amphetamine occurs by two main pathways oxidative deamination or aromatic hydroxylation. In the human, rabbit, and guinea pig. oxidative deamination appears to be the predominant pathway in the rat. aromatic hydroxylation appears to be the more important route. Phenytoin is another drug that shows markeii species differences in metabolism. In the human, phenytoin undergoes aromatic oxidation to yield primarily (5K-)-/r-hydioxyphenytoin in the dog. oxidation occurs to give mainly (If)(-1-)-iM-hydroxyphenyt-oin. There is a dramatic difference not only in the pasition (i.e.. meta or para) of aromatic hydroxylation but also in which of the two phenyl rings (at C-S of phenytoin) undergoes aromatic oxidation. 

Finally, species differences in the induction of individual or multiple biotransformation and elimination pathways can lead to the production of different metabolite profiles in humans compared to animal models. The FDA... 

Moreover, biotransformation of secondary arylalkylamines also affords nitrones. Thus, N-oxygenation of a series of 4-substituted iV-benzylanilines in liver microsomal preparations from various animal species has been detected to be a minor pathway of metabolism, usually generating a,7V-diphenylnitrones (34) in a species-dependent manner26. Nitrone formation was most abundant in liver, kidney and lung53. There was a clear sex difference... 

Meuldermans et al. [12] presented a complete study on the metabolic pathways of SUF and ALF from the excreta of rats and dogs. Among other techniques, they used GC MS in El and PCI modes for the characterization of major metabo lites after derivatization by silylation or acylation. The same laboratory [13] has identified the two major metabolites of ALF in human urine. Lavrijsen et al. [14] have studied the biotransformation of SUF in vitro in different species using GC-MS in El mode, but also with desorption Cl and Townsend discharge ionization. Several metabolites were identified unambiguously on the basis of their MS data, in comparison with the mass spectra of authentic reference compounds. 

Important kinetic differences and variations in the quantitative as well as qualitative metabolic profiles have been shown between species, thus making extrapolation from one species to another very difficult. All of the metabolic transformations include multiple and separate pathways with demethylation to dimethyl- and monomethylxanthines, formation of dimethyl- and monomethylurates, and ring opening yielding substituted diaminouracils (Figure 2). The reverse biotransformation of theophylline to caffeine is demonstrated not only in infants but also in adults. 

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