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Disposition and behavioral effects of amphetamine and β,β-difluoroamphetamine in mice

1972; Elsevier BV; Volume: 21; Issue: 9 Linguagem: Inglês

10.1016/0006-2952(72)90291-2

1873-2968

Ray W. Fuller, Bryan B. Molloy, Betty W. Roush, Kenneth M. Hauser,

Alcohol Consumption and Health Effects

Abstract β, β-Difluoroamphetamine, which has a lower p K value than amphetamine and so exists at physiological pH predominantly as a neutral molecule rather than as a cation, localized in epididymal fat to a greater degree than in brain in mice, in contrast to amphetamine. Difluoroamphetamine had a much shorter half-life in brain (19 min) than did amphetamine (51 min), and the half-life was not affected by a 4-chloro substituent (18 min), in contrast to that of amphetamine (261 min for 4-chloroamphetamine). The half-life of difluoroamphetamine and of 4-chloro-difluoroamphetamine was essentially the same in fat as in brain (16 and 20 min respectively). Due to its different distribution and its shorter half-life, difluoroamphetamine had to be given at higher doses to maintain brain levels comparable to those of amphetamine. Likewise, higher doses of the difluoroamphetamine were required for equivalent degrees of central nervous system (CNS) stimulation as measured by increased locomotor activity. The duration of CNS stimulation was shorter for difluoroamphetamine than for amphetamine, correlating with the more rapid removal of the former compound from brain. Two inhibitors of microsomal drug-metabolizing enzymes, 2,4-dichloro-6-phenylphenoxyethylamine (DPEA) and β-diethylaminoethyldiphenylpropylacetate (SKF 525-A), caused increased brain levels of difluoroamphetamine but not amphetamine, and desmethylimipramine (DMI) did not affect brain levels of either drug. The results suggest an alteration in metabolism as well as in tissue distribution resulting from the decreased basicity of the β, β-difluoro compound.