covering a wide range of MW (150 to>700) demonstrated an increase in the
proportion of compounds excreted in the bile vs. urine as the MW increased [see
Calabrese ( 1983 ) for a review]. Urinary excretion accounts for almost all the
elimination of compounds having a MW<250, whereas it becomes negligible
for compounds with MW>600–800. The same phenomenon has been reported in
other species but with some differences in ranges of MW. Substances with low
molecular weights (MW<300) are primarily eliminated by renal clearance (glo-
merular filtration) in most species; substances (drug, metabolites, conjugates) with
MW>600 are typically eliminated in the bile by active carrier-mediated transport.
For substances having MWs between 300 and 600–800, the preferential route of
elimination may show large species differences and it is for this MW range that the
likelihood of interspecies differences is the highest, with so-called poor biliary
excreters (rabbits, ginea-pigs, man), good biliary excreters (rats, chickens, dogs)
and intermediate species (cats, sheep) having been classified. These species differ-
ences arise from the fact that the value of the threshold MW for appreciable biliary
excretion varies from species to species. It should be stressed that the definition of
poor or good biliary excreters is not related to the rate of bile flow, which is very
high in rabbits (90 mL/min/kg), a so-called poor biliary excreter, and much lower in
dogs (4–10 mL/min/kg), a so-called good bile excreter.
For liver metabolism, the hepatic clearance is given either by (3) or (4) for
substances having a low or a high extraction, respectively:
CLhm¼fuClint¼fuVmax
Km; (3)
CLhm¼Qh_ : (4)In (3), the elimination by the liver of drugs having a low extraction ratio has only
two determinants: the extent of binding to circulating plasma proteins as expressed
byfu, the unbound fraction (from 0 to 1) and Clint, the intrinsic clearance which is
determined by the ratio of the maximal metabolic capacity (Vmax) andKm, the
parameter that expresses the affinity of a substance for the metabolic enzymes.Vmax
is related to the nature of the enzymes (e.g. different families of P450 cytochromes)
and interspecies differences in hepatic metabolism can be explained in terms of
Vmax. For drugs with a high extraction ratio (4), the clearance is equal to the hepatic
blood flow (first pass effect) and for these drugs interspecies differences reflect
differences in hepatic blood flow (that area priori known) and not of drug
specificities. Therefore, it is for drugs having a low extraction ratio that the most
important interspecies variability is expected, because the P450 cytochromes (i.e.
Vmax) can vary considerably from species to species (vide infra).
Even in closely related species, major differences may exist, for example
between horses (Equus caballus) and donkeys (Equus asinus). Thus, for phenylbu-
tazone (PBZ), the plasma clearance is about 10 times higher in donkeys than in
horses. Therefore, to achieve the same PBZ exposure in the two species, the dose
Species Differences in Pharmacokinetics and Pharmacodynamics 31