Excretion species differences

Tlie approacli in tliis chapter is to consider first the chemical and then tile biological factors in the biiiary excretion of organic compounds. The types of compound excreted in the bile will be discussed from the point of view of relating eiiemieal structure to biliary excretion. One important biological factor is metabolism, because most substances undergo metabolic cliange in the body, and for certain compounds, this produces metabolites ivith the necessary structural factors for extensive biliary excretion. Species differences in biliary excretion are then de.scribed, and finally, some po.ssible reasons for these differences are discussed. 

Intravenous administration of endosulfan (7 3 ratio of a- and P-isomers) in rabbits produced slower elimination of the a-isomer (Gupta and Ehrnebo 1979). Excretion of the two isomers occurred primarily via the urine (29%) with much less excreted via the feces (2%). Given the earlier evidence in rats and mice describing the principal route of elimination of endosulfan and its metabolite to be via the feces, the differences in the excretion pattern in this study may be attributable to differences in exposure routes, to species differences, or to both. Nevertheless, studies in laboratory animals suggest that both renal and hepatic excretory routes are important in eliminating endosulfan from the body. Elimination of small doses is essentially complete within a few days. 

Tomokuni K, Ichiba M, Hirai Y. 1988. Species difference of urinary excretion of delta-aminolevulinic acid and coproporphyrin in mice and rats exposed in lead. Toxicol Lett 41 255-259. 

Urinary excretion patterns of thiocyanate suggest that there are quantitative species differences in acrylonitrile metabolism (Ahmed and Patel 1981). Thiocyanate was identified as a metabolite in rats, mice, rabbits and Chinese hamsters. About 20 to 23% of the administered dose was excreted as thiocyanate in rats, rabbits and Chinese hamsters, while 35% was excreted as thiocyanate in mice (Gut et al. 1975). It has also been observed that mice metabolize acrylonitrile more rapidly than rats (Ahmed and Patel 1981 Gut et al. 1975). Maximum blood cyanide concentrations were observed 1 hour after dosing in mice, but 3 hours after dosing in rats (Ahmed and Patel 1981). In mice, thiocyanate was present in the urine within 4 hours of dosing, while in rats, thiocyanate was present in urine only at time intervals longer than 4 hours (Gut et al. 1975). 

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of acrylonitrile in rats has been studied. Limited work in other species suggests that important species differences do exist. Further evaluation of these differences, and comparison of metabolic patterns in humans with those of animals would assist in determining the most appropriate animal species for evaluating the hazard and risk of human exposure to acrylonitrile. 

Species Differences. Species differences in metabolism are amongst the principal reasons that there are species differences in toxicity. Differences in cytochrome P450 is one of the most common reasons for differences in metabolism. For example, Monostory et al. (1997) recently published a paper comparing the metabolism of panomifene (a tamoxifen analog) in four different species. These data serve to address that the rates of metabolism in the non-human species was most rapid in the dog and slowest in the mouse. Thus, one should not a priori make any assumptions about which species will have the more rapid metabolism. Of the seven metabolites, only one was produced in all four species. Both the rat and the dog produced the two metabolites (M5 and M6) produced by human microsomes. So how does one decide which species best represents humans One needs to consider the chemical structure of the metabolites and the rates at which they are produced. In this particular case, M5 and M6 were relatively minor metabolites in the dog, which produced three other metabolites in larger proportion. The rat produced the same metabolites at a higher proportion, with fewer other metabolites than the dog. Thus, in this particular instance, the rat, rather than the dog, was a better model. Table 18.8 offers a comparison of excretion patterns between three species for a simple inorganic compound. 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Species differences in the metabolism of propachlor are summarized in Table II. All species studied metabolized propachlor in the MAP. Obvious, but unexplained differences are that the rat excreted no cysteine conjugate and the chicken formed no methylsulfonyl-containing metabolites. The absence of methylsulfonyl formation by chickens is thought due to the low biliary secretion of first pass metabolites. The ruminant (sheep) excreted large amounts of cysteine conjugate in urine which is also not explained. We do not know if the intestinal flora are involved in the formation of the methylsulfonyl acetanilides isolated from sheep urine. 

Piperazine and its salts are readily absorbed from the gastrointestinal tract, but nitrosation may occur in the stomach (32). The major portion of the absorbed drug is metabolized in tissues and the remainder, which is about 30-40%, is excreted in the urine. Piperazine is detectable in the urine as early as 0.5 h after drug administration. Although there is a wide variation in the rates at which piperazine is excreted by different animal species, urinary excretion is practically complete within 24 h. 

The excretion of a foreign substance can also be a major factor in its toxicity and a determinant of the plasma and tissue levels. All these considerations are modified by species differences, genetic effects, and other factors. The response of the organism to the toxic insult is influenced by similar factors. The route of administration of a foreign compound may determine whether the effect is systemic or local. 

The species pattern of the rabbit and the guinea pig being poor biliary excretors and the rat being an extensive biliary excretor is maintained with many other compounds. With compounds of higher molecular weight, however, species differences are less, as illustrated by the compound indocyanine green (Table 5.8). The metabolism of a compound obviously influences the extent of biliary excretion, and therefore species differences in metabolism may also be a factor. 

However, there are known instances of differences in the preferred route of metabolism, which are important in toxicity, as well as simple differences in the route of a particular oxidation. For example, the oxidative metabolism of ethylene glycol gives rise to either carbon dioxide or oxalic acid (Fig. 5.7). The relative importance of these two pathways is reflected in the toxicity. Thus, the production of oxalic acid is in the order cat>rat> rabbit, and this is also the order of increasing toxicity (Fig. 5.8). The aromatic hydroxylation of aniline (Fig. 5.9) shows marked species differences in the position of substitution, as shown in Table 5.9. Thus carnivores such as the ferret, cat, and dog excrete mainly o-aminophenol, whereas herbivores such as the rabbit and guinea pig excrete mainly p-aminophenol. The rat, an omnivore, is intermediate. 

A recent example of a species difference in metabolism causing a difference in toxicity is afforded by the alicyclic hydroxylation of the oral antiallergy drug, proxicromil (Fig. 5.11). After chronic administration, this compound was found to be hepatotoxic in dogs but not in rats. It was found that dogs did not significantly metabolize the compound by alicyclic oxidation, whereas rats, hamsters, rabbits, and man excreted substantial proportions of metabolites in the urine. In the dog, biliary excretion was the route of elimination of the unchanged compound,... 

Abou-EI-Makarem MM, Millburn P, Smith RL, et al. Biliary excretion in foreign compounds. Species difference in biliary excretion. Biochem J 1967 105 1289-1293. 

The kinetics of the excretion of various silver compounds are well characterized in animals and limited human data exist for inhalation and oral exposure. Further study into (1) the underlying basis for observed species differences (2) quantitation of the elimination of dermally absorbed silver compounds and (3) the basis for observed interpersonal differences in tolerance would aid in identification of human subpopulations with varying susceptibilities to the toxic effects of silver. 

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