720 
PHARMACOLOGY 
persistence of the drug was observed in any 
species studied. 
The extent of plasma protein binding of am- 
phetamine was independent of drug concentra- 
tion over the range of concentrations observed 
in vivo (25-400 ng ml~^). At a drug concen- 
tration of 10 ~^ Molar the mean percent bind- 
ing of amphetamine was 40.7, 39.6, 25.3, 31.0, 
14.5, 27.1, 26.4, 40.5, 40.2, 26.0 for goats, swine, 
ponies, rabbits, chickens, dogs, cats, rats, mon- 
keys and opposum respectively. Table VIII. The 
extent of plasma protein binding of amphet- 
amine differed significantly between species (F- 
test, p<0.01). 
These protein binding values were employed 
in correcting the apparent specific volumes of 
distribution of the drug. The corrected volumes 
of distribution were large in all species, the val- 
ues obtained for the porcine, equine, lapine and 
canine species were similar (ca. 3.5 litres/kg). 
The ruminant animals had a particularly large 
apparent volume of distribution (5.19 litres/ 
kg) which may have been due to passive dif- 
fusion into the rumen of some of the unbound 
nonionized portion of circulating drug. Cats and 
chickens, on the other hand, had smaller vol- 
umes of distribution for this drug than those es- 
timated for the other animals. The value of k2 
relative to ft was directly related to the appar- 
ent specific volume of distribution of the drug. 
The wider the k2 :/3 ratio the shorter the biolog- 
ical half-life. In goats the value of kz was one 
hundred times that of /3 while in cats k2 was 
fifty times /3. 
The quantities of unchanged amphetamine, 
Table VIII. — Total Plasma Protein Concentration and 
Extent of Protein Binding of Amphetamine in Va- 
rious Species of Animals 
Amphetamine concentration: 10—° Molar 
% bound Plasma protein 
amphetamine cone. (g%) 
Species 
Mean S.E.M. 
Mean S.E.M. 
Equine (9) 
25.3 
2.6 
7.5 0.3 
Caprine (12) 
40.7 
1.7 
6.6 0.3 
Porcine (6) 
39.6 
3.0 
6.4 0.6 
Canine (17) 
27.1 
1.5 
6.7 0.3 
Feline (12) 
26.4 
1.2 
7.3 0.2 
Lapine (4) 
31.0 
2.9 
5.5 0.3 
Avian (6) 
14.5 
0.9 
3.0 0.3 
Monkey (11) 
40.2 
0.7 
7.8 0.2 
Opossum (4) 
26.0 
4.0 
6.8 0.4 
Rat (4) 
40.5 
3.0 
6.1 0.8 
p-hydroxyamphetamine and its glucuronide and 
sulphate conjugates in cumulative urine sam- 
ples were measured. A relationship appeared to 
exist between dietary habit and metabolic pat- 
tern of amphetamine. Approximately one-third 
of the amphetamine injected was excreted un- 
changed in the urine of carnivorous animals 
and chickens while a small percentage of the 
dose was excreted unchanged in the urine of 
herbivorous animals. The amount of ampheta- 
mine which is eliminated by renal excretion, that 
is, the magnitude of the contribution of 
kexcrption to k2, may be of importance in deter- 
mining the effectiveness of urinary pH change 
upon the biological half-life of this drug. The 
urinary pH reaction had a profound effect upon 
the renal clearance and directly influenced the 
biological half-life of amphetamine in dogs. The 
renal clearance values provided evidence that 
amphetamine was probably filtered and then 
reabsorbed by glomerular filtration and tubular 
reabsorption. In horses the biological half-life 
was not significantly influenced (Student's "t" 
test, p(<0.05) by any urinary pH reaction. 
The biliary clearance values and the cumula- 
tive amount of unchanged amphetamine in bile 
(dogs and swine) indicated that this pathway 
played a minor role in the elimination of this 
drug from the body. 
Quinidine 
The disappearance of quinidine from the 
blood plasma of the various species is shown in 
Figure 5. First-order kinetics were followed in 
all species. The most remarkable feature of 
these data, aside from differences in slopes of 
the various curves, is the high plasma concen- 
trations of the drug in swine. 
Values for kinetic constants are tabulated in 
Table IX. The plasma half-life was shortest in 
goats and longest in dogs and swine. On extrap- 
olating to zero time, the mean values for Co 
(drug concentration at zero time) varied from 
2.68 mg/L in goats 9.69 mg/L in swine. Values 
obtained in ponies were not comparable because 
the dose of quinidine administered was half 
that given to the other species. Values for V'd 
(apparent specific volume of distribution) var- 
ied among the different species and were indica- 
