THE PHARMACOKINETICS OF AMPHETAMINE 
IN DOMESTIC ANIMALS 
J. D. Baggot and L. E. Davis* 
The objective of this work was to determine the 
pharmacokinetic constants describing the distribution 
and elimination of amphetamine in different species of 
domestic animals. The species studied were ponies, 
goats, swine, dogs, cats, rabbits and chickens. A similar 
dose (0.66 mg/kg) of dZ-amphetamine sulphate was 
administered i.v. to each experimental subject. Amphet- 
amine concentrations in biological fluids (blood 
plasma, cerebrospinal fluid, urine and bile) were meas- 
ured by a sensitive and specific gas chromatographic 
method. The drug attained distribution equilibrium very 
rapidly and elimination was first-order in all species. 
Plasma half-life values varied from 0.62 hour in goats 
to 6.53 hours in cats. The mean biological half-life of 
the drug varied significantly among species (F-test, 
p<0.01). Extent of plasma protein binding (in vitro) 
was determined by equilibrium dialysis technique. The 
percent amphetamine bound to plasma proteins was in- 
dependent of drug concentration within the range of 
concentrations observed in vivo (25-400 ng ml"*). 
Extent of binding was low (<41%) in all species but 
varied significantly among species (F-test, p<0.01). 
The apparent specific volumes of distribution of the 
drug, corrected for extent of plasma protein binding, 
were large (>2.1 litres/kg) in all species, this indi- 
cated extensive tissue distribution and sequestration. 
Approximately one-third of the amphetamine injected 
was excreted unchanged in urine of carnivorous ani- 
mals and chickens while a small percentage of the dose 
was excreted unchanged in urine of herbivorous ani- 
mals. The mean biological half-lives of the drug were 
significantly different in intact and nephrectomized dogs 
(Student's "t" test, p<0.001). Biliary excretion of un- 
changed drug was low. A relationship appeared to exist 
between dietary habit and elimination of amphetamine. 
Elimination was significantly slower in carnivorous 
species than in the herbivorous and omnivorous species 
studied. 
INTRODUCTION 
The amphetamine molecule has a simple 
chemical structure, diffuses rapidly into tissues 
* Division of Comparative Pharmacology, College of Veterinary 
Medicine, The Ohio State University, Columbus, Ohio 43210. 
of high blood perfusion, undergoes a complex 
metabolic fate, and markedly alters the physio- 
logic disposition of norepinephrine. The drug is 
eliminated from the body by excretion and 
biotransformation. Amphetamine (2-amino-l- 
phenylpropane) can be metabolized along two 
major pathways, either by hydroxylation of the 
aromatic ring to p-hydroxyamphetamine or by 
deamination of the side chain to 1-phenylpro- 
pane-2-one (benzyl methyl ketone), which can 
then be degraded to benzoic acid. These two 
pathways are shown to occur and their relative 
extent appeared to vary with species. ^"^ A 
minor pathway for amphetamine metabolism 
involved /3-hydroxylation this was catalyzed 
by the enzyme dopamine /S-oxidase.^^' Little is 
known, however, about the species distribution 
of the /3-hydroxylation reaction.^^ 
The pKa value of d-amphetamine is 
9.90;i2,i3 iiii^ implies that at the physiological 
pH only a small fraction (0.31 per cent) is in 
the neutral or nonionized form. The neutral 
form is reasonably soluble in various organic 
solvents whereas the ionized form is water-solu- 
ble. The lipid-solubility of the neutral form is 
reflected in the so-called true partition coeffi 
cient, for example, hepatane/water 1:88; 
chloroform/ water 1 :46.i* 
The objective of this work was to determine 
the pharmacokinetic constants describing the 
distribution and elimination of amphetamine in 
different species of domestic animals. Prior to 
this study, curves of the decline of plasma am- 
phetamine concentration were not available, so 
it was unknown whether elimination was a sim- 
ple first-order or multiphasic process. Elimina- 
tion refers to all the processes that operate to 
reduce the effective drug concentration in the 
body fluids. 
691 
