Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03-mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03-mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half-life (t½) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t½ by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration-time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding. Clinical Pharmacology and Therapeutics (1980) 28, 368–375; doi:10.1038/clpt.1980.175