Metabolism of amphetamine after acute and chronic administration to the rat

The distribution of amphetamine (AMPH) and its hydroxylated metabolites p-hydroxyamphetamine (POHA), p-hydroxynorephedrine (POHNOR) and p-hydroxyamphetamine glucuronide (POHAG) in various tissues was studied after acute and chronic administration of AMPH to rats. After intraperitoneal administration of a single dose of [3H]AMPH, tissue [3H]AMPH levels increased rapidly to a maximum within 15 to 20 min of administration and then declined biphasically [(t1/2 = 0.5--0.9 hr for the distribution phase (alpha) and 5--9 hr for the elimination phase (beta)]. Tissue [3H]POHA levels and liver [3H] POHAG levels also increased rapidly and then declined exponentially (t1/2 = 4--10 hr for POHA), while tissue [3H]POHNOR increased gradually and declined with a half-life of 18 to 24 hr. The distribution of [3H]AMPH and its 3H-metabolites after a single dose of [3H] AMPH changed significantly after chronic administration of amphetamine. [3H]AMPH content in tissues of chronically treated rats was significantly greater 30 min after [3H]AMPH administration than that observed in tissues of animals not previously treated with AMPH. The disappearance of [3H]POHA from liver and [3H]POHNOR from heart was accelerated and the disappearance of [3H] POHAG from liver was slowed in chronically treated animals relative to controls, while the half-life of [3H]AMPH was unchanged in these animals. Tissue content of both AMPH and POHNOR 12 hr after the last of six doses of AMPH was significantly greater than that observed after a single dose, suggesting that significant accumulation of both compounds occurs during chronic AMPH administration. These studies suggest that the changes in the distribution of AMPH and its active metabolites which occur during chronic AMPH administration might be involved in the altered behavioral response to AMPH observed during such chronic administration.