J. D. BAGGOT AND L. E. DAVIS 
695 
Table IV. — The Dose of Amphetamine Injected I.V., 
the Biological Half-life of the Drug and the Cumula- 
tive Amounts of Amphetamine Excreted in Urine and 
Bile of Swine 
Total Urine pH Cumulative amount of 
Subject dose mean value ti/2 amphetamine (3 hr) 
pig (mg) (range) (hr) Urine (mg) Bile (^g) 
PB 13.2 5.87 0.93 1.08 14.4 
(5.71-6.05) 
PC 16.2 5.82 1.14 1.36 20.3 
(5.61-5.76) 
PX 11.8 6.07 0.92 0.93 14.9 
(5.88-6.34) 
biological half-life of the drug, and the cumula- 
tive amounts of unchanged amphetamine ex- 
creted in urine and bile of individual dogs are 
tabulated in Table V. No attempt was made to 
control urinary pH; the observed values were 
within the normal range for the canine species. 
Despite individual differences in biological 
half-life there appears to be a direct relation- 
ship between urinary pH and the biological 
half -life of this drug; the more acid the urine, 
the shorter the biological half-life. The renal 
clearance values in dogs (2.8 to 5.1 ml min"^ 
kg~^) provided evidence that amphetamine 
probably undergoes glomerular filtration and 
tubular reabsorption. The amount of unchanged 
AMPHETAMINt , mg. 
^ O P 
o 00 N) o) 
r.-l 1 1 L 1 
2 
m 
OJ- 
00 Fo o5 
AMPHETAMINE pg. 
Figure 2. — The cumulative appearance of amphet- 
amine in urine O O (mg) and bile A A (^g) 
of swine following the intravenous injection of am- 
phetamine sulphate (0.66 mg/kg, free base). Each 
point represents the mean amount of amphetamine in 
the biological fluid of three animals. 
amphetamine in urine was approximately five 
hundred times the amount present in bile in 
each experimental subject. A substantial por- 
tion of the dose was excreted in the urine of 
man unchangedj^^.s? and. urinary pH was an 
important factor in determining the rate of 
excretion of this drug.^^.ss in man, amphet- 
amine was cleared from blood more rapidly than 
could be accounted for by glomerular filtration 
under acid conditions, but when urinary pH fluc- 
tuated, clearance of the drug could be accounted 
for by this route.^*' Unlike man and the dog, 
the biological half-life of this drug in the horse 
was independent of urinary pH. This was prob- 
ably due to the small amount of nonionized 
amphetamine available for renal tubular reab- 
sorption. 
The quantities of unchanged amphetamine, 
p-hydroxyamphetamine and its glucuronide and 
sulphate conjugates in cumulative urine sam- 
ples of the several species are summarized in 
Table VI. Comparison of urinary pH of the 
species suggests that differences in the amount 
of amphetamine excreted unchanged cannot be 
related to variations in urinary pH. Although 
this may be a contributing factor, the rate of 
the principal metabolic pathway for this drug is 
most likely to be the dominant factor determin- 
ing the proportion of the dose excreted un- 
changed. The amounts of the various fractions 
recovered, expressed as percent of the dose ad- 
ministered, are shown in the histogram form 
(Figure 3) . Approximately one-third of the am- 
phetamine injected was excreted unchanged in 
urine of carnivorous animals (dog and cat) and 
the chicken while a relatively small fraction of 
the dose was excreted unchanged in urine of 
herbivorous species (pony, rabbit and goat). 
The low percent of dose recovered in urine of 
ponies (33%) and rabbits (27%) suggested 
that the principal metabolite was not measured. 
Oxidative deamination was shown to be the 
major metabolic pathway for amphetamine in 
the rabbit.i'3.«-8 Swine excreted 15% of the 
dose unchanged and the rat 13% of the dose in 
48 hours.^ The rates of disappearance of am- 
phetamine from plasma of swine and male 
rat^i were similar. Also the principal metabolic 
pathway in these two omnivorous species was 
p-hydroxylation and glucuronidation. 
