Urinary metabolites of phenobarbitone, primidone, and their N-methyl and N-ethyl derivatives in humans.

1. Phenobarbitone (1) and three of its N-alkyl derivatives, and primidone (10) and four of its N-alkyl derivatives, were orally administered separately to two human volunteers. Total urine was collected for approximately 2 weeks following each dose, and the drugs and their metabolites were assayed by g.l.c.-mass spectrometry. 2. Recoveries in the phenobarbitone series increased from approximately 40% to approximately 50% as alkylation of (1) increased. There was a linear relationship between the extent of p-hydroxylation and the lipophilicity (log P) of the substrates. The increased total recovery was largely attributable to increased p-hydroxylation. 3. Urinary recoveries in the primidone series decreased from approximately 80% for (10) to approximately 30% for its diakyl derivatives, despite a slight increase in p-hydroxylation with increasing alkylation (and increasing lipophilicity). The decreased recovery was mainly the result of decreased urinary excretion of the drug.