Species differences in metabolism

In general, it is easier to use models such as these to predict the distribution of chemicals (i.e., relationship between exposure and tissue concentration) than it is to predict their toxic action. The relationship between tissue concentration and toxicity is not straightforward for a diverse group of compounds, and depends on their mode of action. Even with distribution models, however, the picture can be complicated by species differences in metabolism, as in the case of models for bioconcentration and bioaccumulation (see Chapter 4). Rapid metabolism can lead to lower tissue concentrations than would be predicted from a simple model based on values. Thus, such models need to be used with caution when dealing with different species. 

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. 

Monostory, K., Jemnitz, K., Vereczkey, L. and Czira, G. (1997). Species differences in metabolism of panomifene, an analogue of tamoxifen. Drug Metab. Dispos. 25 1370— 1378. 

Smith, D. (1991). Species differences in metabolism and pharmacokinetics are we close to an understanding Drug Metab. Rev. 23 355-373. 

Interspecies differences in the rate of chloroform conversion were observed in mice, rats, and squirrel monkeys, with species differences in metabolism being highly dose-dependant. The conversion of chloroform to carbon dioxide was highest in mice (80%) and lowest in squirrel monkeys (18%) (Brown et al. 1974a). Similarly, chloroform metabolism was calculated to be slower in humans than in rodents. Therefore, it was estimated that the exposure to equivalent concentrations of chloroform would lead to a much lower delivered dose in humans (Corley et al. 1990). 

Albro PW, Corbett JT, Schroeder JL, Jordan S, Matthews HB (1982) Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP. Environ Health Perspect 45 19-25... 

The greater sensitivity in mice than in rats to induction of carcinogenesis is likely related to species differences in metabolism to the active epoxide metabolites. ... 

Food Chain Bioaccumulation. Bioconcentration factors have been determined for algae, shellfish, and fish and exhibit a wide range (29-17,000) (ERA 1976 Oliver and Niimi 1983 Pearson and McConnell 1975). This wide range may be explained in part by species differences in metabolism or differences in concentrations tested. Studies also indicate that hexachlorobutadiene preferentially accumulates in the livers of fish. Further studies which might explain the wide range of BCF values would be helpful. No information was located regarding the bioaccumulation of hexachlorobutadiene in plants or aquatic organisms. More information is needed to determine the importance of terrestrial/aquatic food chain bioaccumulation as a potential human exposure pathway. 

The National Research Council (NRC) published a report, Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for assessing of cancer risks. These general guidelines can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene indicates that two default options may no longer be tenable Humans are as sensitive as the most sensitive animal species and the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. 

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. 

Examples of toxicologically important species differences in metabolism will therefore be dealt with by considering the different types of metabolic reactions. 

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,... 

Concluding remarks. Thus most species differences in metabolism are quantitative rather than qualitative only occasionally does a particular single species show an inability to carry out a particular reaction, or to be its sole exponent. The more common quantitative differences depend on species differences in the enzyme concentration or its kinetic parameters, the availability of cofactors, the presence of reversing enzymes or inhibitors, and the concentration of substrate in the tissue. 

Species differences in metabolism are mainly found in phase 2 reactions. 

Johanson, G. Filser, J.G. (1996) PBPK model for butadiene metabolism to epoxides quantitative species differences in metabolism. Toxicology, 113,40-47... 

As early as possible, assess species differences in metabolism of a drug (in vitro studies, nonclinical animal studies). 

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. 

Introduction — This chapter summarizes significant contributions from the drug metabolism literature of the past year, with the objective of illustrating how pharmacokinetic and biotransformation information can assist in the discovery and development of new drugs. The format follows closely that of last year. The influence of structural alterations on drug disposition, metabolic events that lead to pharmacologically active or toxic substances, advances in novel or little studied biotransformations, and species differences in metabolism are discussed. 

Some important conclusions emerge even from this rudimentary profile of mechanisms. Metabolism is as significant in carcinogenesis as jt is in the production of other forms of toxicity, so a thorough evaluation of risk would require knowledge of species differences in metabolism, arid the influence of the size of the dose on metabolic behavior. 

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