Allometric scaling of clearance is least successful for metabolically cleared drugs with low extraction. This is perhaps hardly surprising, as these compounds will be most sensitive to the subtle differences in the affinities of species-specific homologues of the enzymes of metabolism. In these cases the clearance in man is generally lower than would be predicted by straightforward allometry. By including a factor, which reflects the reduced rate of maturation in man, these differences can be corrected. Such factors have included maximum life span potential (MLP) and brain weight .
Compounds which are substrates for mixed function oxidase enzymes, including P450s, tend to show lower than expected clearance in man based upon the simple allometric scaling incorporating body weight alone. This may be correlated with the enhanced longevity of man compared to most animals, since the faster the pace of life, the shorter it is. Hence slowing the metabolic rate, including that of the mixed function oxidases, allows the MLP to be extended. This reflects a major evolutionary advantage of man over other animal species. Therefore incorporation of MLP into the allometric extrapolation provides a more accurate assessment of physiological time than body weight alone. One additional potential advantage of reduced activity of the mixed function oxidases is decreased activation of pro-carcinogens and decreased free radical formation, hence prolonging life span.
The consideration of clearance in units of volume per maximum life span potential, instead of the traditional volume per weight, provides an allometric relationship for drugs such as antipyrine and phenytoin . Both of these drugs are essentially low clearance compounds, cleared by P450 metabolism. Ultimately, the successful utility of such factors may be purely serendipitous as they simply exploit unique features of man as a species.
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