Phenytoin: an inhibitor and inducer of primidone metabolism in an epileptic patient.

Abstract

The interaction between primidone and phenytoin was studied in an epileptic patient treated with primidone only and primidone plus phenytoin for 3 months. Plasma and urine levels of drugs and metabolites were monitored daily by GC and GC-MS. The addition of phenytoin to the regimen increased steady-state plasma levels of phenobarbitone and phenylethylmalonamide (PEMA), metabolites of primidone, and decreased levels of primidone and unconjugated p-hydroxyphenobarbitone (p-OHPB), a metabolite of phenobarbitone. After withdrawal of phenytoin, plasma phenobarbitone and primidone levels slowly returned to previous steady-state levels, PEMA rapidly decreased to lower levels than before, and p-OHPB levels rose rapidly. Urinary excretion of primidone and its metabolites paralleled the changes in their plasma levels after the addition of phenytoin but the percentage of unconjugated p-OHPB in urine was unchanged during the course of the study. In conclusion phenytoin initially induces the conversion of primidone to PEMA and phenobarbitone, although each to a different extent, but it appears to inhibit the hydroxylation of phenobarbitone. Thus, two apparently contradictory phenomena seem to be involved in the primidone-phenytoin interaction. The net effect is an enhanced increase in plasma phenobarbitone levels.