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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
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9.2 Allometric Scaling 127
Fig. 9.2 Allometric relationship between body weight and systemic clearance of fluconazole.
0 1 Log BW (kg)
Thus everything occurs more rapidly in the rat than in man and “physiological time” is shorter (on a chronological scale) the smaller the species. Hence physiological processes that are dependent upon time become disproportionately more rapid in smaller species. This is illustrated by the allometric analysis of creatinine clearance (a measure of glomerular filtration rate) which shows an allometric exponent of 0.69. A similar allometric exponent is obtained for the clearance of fluconazole (Figure 9.2), a compound that is almost exclusively cleared by the kidneys. Hence whilst weight normalized clearance may decrease from 4 mL min-1 kg-1 in mouse to 0.3 mL min-1 kg-1 in man, an allometric relationship is observed across the different species with an exponent of 0.73. This value for the exponent is in keeping with the general observation for small organic molecules where successful predictions are associated with an exponent value of about 0.75 [8]. Thus clearance of fluconazole remains relatively constant across species with respect to “physiological time”, as renal clearance remains a constant fraction of the glomerular filtration rate (GFR) at about 20% [9].
As with the allometric relationship with volume of distribution, fluconazole exhibits only low plasma protein binding and for compounds which exhibit variation in protein binding across species, allometry should be based upon clearance of unbound drug. Amongst other drugs cleared by the kidneys which show an allometric relationship, the a1-adrenoceptor antagonist, metazosin, is notable in that the allometric exponent for clearance is 0.28 [12]. Together with the unusual allometric exponent of 0.6 for volume of distribution this clearly suggests some abnormality in the disposition of this compound which has not yet been explained.
When clearance is dependent upon metabolism, species-specific differences in the enzymes of metabolism can clearly prevent any such allometric relationship. An example of this is the absence of a close homologue of the human CYP2C9 enzyme in the dog, hence its inability to hydroxylate drugs such as tolbutamide and tienilic acid [13]. This said, many compounds cleared by metabolism do exhibit allometric relationships (e.g. N-nitrosodimethylamine, [14]). In an extensive analysis of the allometric relationship between clearance in the rat and man for 54 extensively cleared
128 | 9 Inter-Species Scaling
drugs, the mean allometric exponent value was 0.66 [15]. This analysis also confirmed the improved correlation when unbound plasma clearance was considered.
9.3 Species Scaling: Adjusting for Maximum Life Span Potential
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 homo-logues 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 [16].
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 [17]. 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.
9.4 Species Scaling: Incorporating Differences in Metabolic Clearance
An alternative approach to relying simply upon allometric approaches for metaboli-cally-cleared compounds is to take into consideration their relative stability in vitro. Clearance by P450 enzymes observed in hepatic microsomes from different species provides a measure of the relative intrinsic clearance in different species. Using the equation for the well-stirred model:
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