Species, differences in drug metabolism

Caldwell J. The current status of attempts to predict species differences in drug metabolism. Drug Metab... 

What is the underlying cause for these interspecies differences For equal doses, differences in plasma AUC values simply indicate differences in total body clearance. Renal and metabolic elimination processes are the major contributors to total body clearance. When allometric scaling is used as described in Chapter 30, renal clearance tends to exhibit only small differences across species, whereas there are many examples of interspecies differences in metabolism. Further, across many drug categories, metabolism is quantitatively more important than is renal elimination. Therefore, more emphasis on inter species differences in drug metabolism could improve Phase I studies. The next two sections provide specific examples of the impact of monitoring metabolism during early human studies. 

Because of the known species-species differences in drug metabolism, it is now believed that in vitro, human-based, experimental systems are more appropriate than nonhuman animal models for the evaluation of drug-drug interactions. In vitro positive findings are usually confirmed with in vivo clinical studies. The typical preclinical studies for drug-drug interactions follow. 

CALABRESE, E.J. (1985) Toxic Susceptibility Male/Female Differences (New York John Wiley). CALDWELL, J. (1981) The current status of attempts to predict species differences in drug metabolism. DrugMetab. Rev., 12, 221. 

Most species differences in drug metabolism, however, result from differences in the rates of enzymatic convosions. For example, a dose of 50 mg/kg of hexo-barbital produces anaesthesia in man or dog for over S hr but 100 mg/kg produces anaesthesia for 90 min in rats, for 49 min in rabbits and for only 12 min in mice. At the time of recovery from anaesthesia, the several animal spedes have remarkably similar brain barbiturate levels. Thus, the duration of action of hexo-barbital in several species is generally proportional to its biologic half life and inversely proportional to the rate of hexobarbital metabolism by enzymes in hepatic microsomes. 

Species differences in drug metabolism make a reliable extrapolation of drug behavior from animal to man very difficult and show the importance of carrying out metabolic studies in man. However, it has been shown for a number of drugs, that a valid projection of activity as well as toxicity from animal to man is possible when drug responses are related to plasma levels rather than dose... 

Species differences in the metabolism of drug may be due to the difference in the rate of metabolism or in their metabolites difference. Certain drugs have been found safe and non-toxic in animals, but when they were tested in human beings severe toxic effects were observed. For example, when sulfanilamide was tested in dog it was found safe and non-toxic, but when it was administered to human being, certain toxic effects like the hematuria, renal failure were observed. 

Kawashima K, Hosoi K, Naruke T, et al. Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic, zaleplon, between monkeys and rats. Drug Metab Dispos 1999 27 422-428. 

A. E. Mutlib, H. Chen, G. A. Nemeth, J. A. Markwalder, S. P. Seitz, L. S. Gan, and D. D. Christ, Identification and characterization of Efavirenz metabohtes by hquid chromatography/mass spectrometry and high field NMR Species differences in the metabolism of Efavirenz, Drug. Metab. Dispos. 27 (1999), 1319-1333. 

Mutlib AE, Chen H, Nemeth GA, Markwalder JA, Seitz SP, Gan LS, Christ DD. Identification and characterization ofefavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR species differences In the metabolism ofefavirenz. Drug Metab Dispos 1999 27 1319-1333. 

Thus far the discussion has been directed toward the general similarities of drug metabolism in animals and man. The qualitative differences in drug metabolism have been discussed by many authors [20, 22-25] and it would seem profitable to examine the major metabolic transformation routes and their relative activities in various species. 

Shimada, T., M. Shindo, and M. Miyazawa, 2002. Species differences in the metabolism of R-(—) and S- +)-limonenes and their metabolites, carveols and carvones, by cytochrome P450 enzymes in hver microsomes of mice, rats, guinea pigs, rabbits, dogs, monkeys, and humans. Drug Metab. Pharmacokinetics, 17 507-515. 

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