694 
PHARMACOLOGY 
Table II. — Total Plasma Protein Concentration and 
Extent of Protein Binding of Amphetamine in Differ- 
ent Species of Animals 
% bound Plasma protein 
Species amphetamine cone. (g./lOO ml) 
Mean ± S.E. Mean ± S.E. 
Goat (12) 40.7 ± 1.7 6.6 ± 0.3 
Swine (6) 39.6 ± 3.0 6.4 ± 0.6 
Pony (9) 25.3 ± 2.6 7.5 ± 0.3 
Rabbit (4) 31.0 ± 2.9 5.5 ± 0.3 
Chicken (6) 14.5 ± 0.9 3.0 ± 0.3 
Dog (17) 27.1 ± 1.5 6.7 ± 0.3 
Cat (12) 26.4 ± 1.2 7.3 ± 0.2 
Amphetamine concentration: 10"° 
each species are tabulated in Table II. Species 
differences in the extent of protein binding of 
the drug were observed (F-test, p<0.01). At a 
similar drug concentration the extent of bind- 
ing (mean ± S.E.) in dependent and drug 
naive human subjects was 23% ± 1.1 and 26% 
± 1.0, respectively.^'' The extent of binding in 
chickens was lower than in any mammalian 
species ; this feature might be explained by the 
low concentration of plasma proteins in the 
bird. 
The mean percent bound amphetamine for 
each species was used to correct the B values 
for the individual animals within the species. 
The corrected apparent specific volumes of dis- 
tribution were then computed. Dominquez^^ de- 
fined volume of distribution as the volume of 
body fluids which holds the substance in solu- 
tion at the same concentration as the plasma. 
The corrected apparent specific volumes of dis- 
tribution (V'd*) were large in all species 
(Table III), the magnitude of this parameter 
was indicative of extensive tissue distribution 
Table IL. — Extent of Plasma Protein Binding, Cor- 
rected A oparent Specific Volume of Distribution and 
Overall ( Hearance Value of Amphetamine in Different 
Species of Domestic Animals 
10-8 M 
Species % bound V'd» C'„^eraii 
(number) Amphetamine (litre/kg) (ml min-i kg-i) 
Goat (10) 40.7 5.19 96.7 
Swine (9) 39.6 3.69 40.6 
Pony (B) 25.3 3.43 29.1 
Rabbit (4) 31.0 3.32 27.4 
Chicken (8) 14.5 2.12 14.6 
Dog (11) 27.1 3.66 9.2 
Cat (6) 26.4 2.49 4.4 
V'd* = Apparent specific volume of distribution corrected for ex- 
tent plasma protein binding of drug 
*^'oT6raii ('•^■> overall clearance value per kilogram) — ^ x V'd* 
and sequestration of the drug. Axelrod^ exam- 
ined the distribution of d-amphetamine in rep- 
resentative tissues of a dog which was given 10 
mg/kg of the drug intraperitoneally. The ani- 
mal was sacrificed one hour after the drug was 
administered. The drug was found to be distrib- 
uted in most organ tissues but only negligible 
amounts were present in fat and bile. Similar 
tissue distributions of this drug were reported 
in the mouse,2« rat,^^ and cat.22 Most of the 
drug was shunted toward tissues of high blood 
perfusion, that is, kidneys, lungs, brain and 
liver. The very large apparent specific volume 
of distribution in goats (5.19 litres/kg) was be- 
lieved to be due to rapid diffusion and subse- 
quent trapping of amphetamine in the rumen. 
The concentration of amphetamine was higher 
(ca. 50%) in rumen fluid than in plasma thirty 
minutes after i.v. administration of drug. The 
pH gradient across the reticuloruminal epithe- 
lium (ca. 1 pH unit) would favor a passive 
transfer process, for example, nonionic diffu- 
sion. Ephedrine attained concentrations in 
rumen liquor which were several times greater i 
than the corresponding plasma levels following I 
intravenous infusion of this compound.^^ Quin- i 
ine also diffused from plasma into ruminal fluid j 
and was trapped there.^* j 
The overall clearance value is an estimate of ! 
the sum of the metabolic and excretory clear- j 
ances of drug from plasma water. Values for | 
overall clearance varied from 4.4 ml min"'^ I 
kg~i in cats to 96.7 ml min~^ kg~^ in goats. The j 
overall clearance values in the other species ' 
studied were intermediate between these ex- 1 
tremes. The relative amounts of amphetamine 
excreted in urine and bile of dogs, swine and | 
rats^s indicated that urinary excretion of \ 
unchanged drug was important but biliary excre- ' 
tion was low. The dose of amphetamine admin- 1 
istered, the biological half-life of the drug and \ 
the cumulative amounts of unchanged amphet- | 
amine excreted in urine and bile of individual ^ 
swine are tabulated in Table IV. The mean cu- f 
mulative amounts of unchanged amphetamine | 
excreted in urine and bile were 8.18 and 0.12 
percent of the dose, respectively. The appear- \ 
ances of the drug in urine and bile followed 1 
first-order kinetics (Figure 2). The dose of am- 
phetamine administered, the urinary pH, the 
