Inhibition of phenobarbitone N-glucosidation by valproate

Plasma phenobarbitone concentrations and daily urinary excretion of phenobarbitone and its metabolites p-hydroxyphenobarbitone (conjugated and unconjugated), and [S]-phenobarbitone-N-glucoside were measured under steady-state conditions in two groups of epileptic patients, (i) taking phenobarbitone with or without other drugs, but not valproate (n = 12), and (ii) taking phenobarbitone with other drugs including valproate (n = 8). Mean steady-state plasma phenobarbitone concentrations were 5.9 mg l-1 higher, relative to drug dose, in the patients taking valproate than in those not taking valproate. Urinary excretion of [S]-phenobarbitone-N-glucoside was significantly lower in the group taking valproate (1.9 +/- s.d. 2.0% of phenobarbitone dose vs 16.2 +/- s.d. 9.9%). Urinary excretion of phenobarbitone (23.7 +/- s.d. 9.8% vs 48.2 +/- s.d. 13.6%) and unconjugated p-hydroxyphenobarbitone (5.7 +/- s.d. 3.9% vs 16.0 +/- s.d. 9.1%) was higher in those taking valproate, while conjugated p-hydroxyphenobarbitone excretion was similar in both groups (8.3 +/- s.d. 4.9% vs 6.5 +/- s.d. 2.9%). Valproate appeared to inhibit both the direct N-glucosidation of phenobarbitone and the O-glucuronidation of p-hydroxyphenobarbitone.