Autoinduction of phenobarbital elimination in the dog

The literature provides no clear answer to the question of whether phenobarbital induces its own metabolism. To investigate this, the kinetics of phenobarbital in beagle dogs was examined using six phenobarbital doses (15, 30, 60, 100, 200, and 400 mg/d) for 3-week periods. Plasma concentrations of phenobarbital were measured by gas chromatography with a nitrogen-selective detector. The peak plasma concentrations ranged from 7.2 micrograms/mL with the 15-mg/d dose to 82 micrograms/mL with the 400-mg/d dose. A regression of phenobarbital clearance versus average plasma concentration gave an r2 value of 0.81. A 214% increase in the oral clearance of phenobarbital was obtained at the 400-mg/d dose level compared with the 15-mg/d level. The major determinant of this increased clearance was an increase in the elimination rate constant of phenobarbital from 0.18 h-1 at the 15-mg/d dose to 0.36 h-1 at the 400-mg/d dose. The apparent volume of distribution also tended to increase with dose. From these results it is suggested that one reason for the failure to observe autoinduction for phenobarbital in the past was the relatively low plasma concentrations attained in many experiments. In comparison, antipyrine clearance shows a much greater increase for the same phenobarbital concentrations, indicating that the subset of microsomal enzymes which affect phenobarbital are less sensitive to phenobarbital induction than is the subset affecting antipyrine.