Pharmacokinetic studies with amphetamines-relationship to neuropsychiatric disorders

Abstract

Intravenous administration of 200 mg of amphetamine to 12 human subjects induced a stage of euphoria noticeable for 10–12 hr followed by signs of dysphoria which were noticeable early but reached a maximum at 14 hr after injection and remained for 48 hr. The subjective effects of amphetamine could be blocked by α-methyltyrosine. The duration of this antiamphetamine action was more than 24 hr. Pharmacokinetic studies in amphetamine- dependent subjects using large intravenous doses were undertaken to relate measurable pharmacokinetic parameters to the clinical manifestations of amphetamine abuse such as paranoid psychosis and development of tolerance. Subjects having an acidic urine exhibited a relatively mild psychosis, while the psychotic symptoms were aggravated in patients with an alkaline urine. The plot of plasma half- life against mean urinary pH during the first 20 hr yielded a striking correlation. For every increase in unit of urinary pH, there was an increase of plasma half-life of about 7 hr. The intensity of the psychosis in patients having an alkaline urine appeared to be dependent on the metabolite levels rather than on the plasma levels of unchanged drug. A pH-dependent excretion of p-hydroxyamphetamine was noted, and it was found that this metabolite was eliminated slower than the parent compound. The second major metabolite was norephedrine.