Toxicology of Industrial Compounds

(4.3)
Simplistically it has been suggested that these differences in longevity can
be explained by the assumption that in any one species there is a
predetermined or fixed amount of total ‘body metabolic potential’ and
once this is used up the animal dies (Boddington, 1978). Boxenbaum (1986)
has extrapolated this concept to include intrinsic hepatic metabolism
suggesting that there is a certain quantity of ‘hepatic pharmacokinetic
stuff’ per unit of body weight available in a life-time which can be
interrelated by the formula:
(4.4)
where CL is the unbound clearance, and c is a constant for each compound.
Thus, the longer the animal lives, the slower this ‘stuff’ is used up.
Examination of the data available from 13 disparate compounds
(Table 4.1), where at least four species have been investigated, shows the
MLP correction has produced good results with an exponent b equal to
unity. Thus this would suggest that the relative clearance between species is
directly proportional to their body weight (W) and MLP, and that animal
(CL (A)) and human clearance (CL (H)) can be simply related according to
equation (4.4).
(4.5)
The maximum life potential (MLP) has been calculated for each animal
from Sacher’s formula (equation (4.3)) (mouse=2.7 y, rat=4.7 y, dog=20 y,
rabbit=8 y, monkey=22 y and human=113 y).
For each drug where the appropriate information was available, the
human clearance has been calculated from each species using the above
approaches and compared with that observed (Table 4.2), and the
percentage prediction measured as:
Results
D.BRUCE CAMPBELL 49
The data from 60 different compounds were used in this ongoing analysis
and as could be expected more data were available for the rat (n=47)
compared to mouse (n=27) and dog (n=28), rabbit (n=24), or monkeys
(n=17). In four cases, valproic acid, diazepam, ceftizoxime and
theophylline, different results were found and data have been analysed
separately. For two classes of drugs, β-lactams and benzodiazepines, data
from a number of compounds were available (n=6 and 12, respectively), but
only mean values were used in this analysis to minimise a class of
compounds bias in the results.