Quantitative structure-activity relationships in drug metabolism and disposition: pharmacokinetics of N-substituted amphetamines in humans.

Pharmacokinetic data of 15 N-alkyl-substituted amphetamines in humans have been the object of a retrospective quantitative structure-activity relationship study. The urinary excretion of amphetamines was shown to decrease with increasing lipophilicity; the correlation equations revealed that, for identical lipophilicities, tertiary amines are excreted faster than secondary amines, which are excreted faster than primary amines. The apparent n-heptane-pH 7.4 buffer partition coefficient correlates better with urinary excretion than does the true n-octanol-water partition coefficient, probably because it includes a pKa term that accounts for the fraction of the drug present in the tubules as nonionic species. The N-dealkylation rate increases with increasing lipophilicity of the substrates (enhanced enyzme affinity) but decreases with increasing bulk of the N-substituent that is split off (steric hindrance of initial C alpha-hydroxylation).