1. Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam
- Author
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Stanley A Kaplan, Rudolph Lucek, William A Garland, Ko-Chin Khoo, Wayne A Colburn, Harold G Boxenbaum, Myer Rothbart, Joseph Mendels, Bo H Min, and John J Carbone
- Subjects
Pharmacology ,Phenytoin ,Oral dose ,Adult ,Male ,Benzodiazepinones ,Chemistry ,Metabolic Clearance Rate ,Models, Biological ,Clonazepam ,Single oral dose ,Kinetics ,Phenobarbital ,medicine ,Distribution (pharmacology) ,Humans ,Pharmacology (medical) ,Drug Interactions ,Female ,medicine.drug ,Half-Life - Abstract
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
- Published
- 1980