Module 8. Effect of chronic phenobarbital administration on phenobarbital pharmacokinetics (hepatic enzyme induction and hepatic failure).


Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:


W.R. Ravis, et al: Pharmacokinetics of phenobarbital in dogs given multiple doses. American J. Veterinary Research, 50(8), 1343 - 1347, 1989.

Phenobarbital is given chronically to dogs in order to control epileptic seizures. As time passes, phenobarbital increases hepatic enzymes (induction) to produce an increase in the clearance of phenobarbital itself. Veterinarians should expect that multiple dose rate adjustments will be required in order to maintain relatively constant plasma concentrations of phenobarbital. Hepatic disease or drug interactions may also reduce the efficiency of elimination of the phenobarbital.


Download hepaticenzymes.xlsx, the spreadsheet for this exercise. Depending on your settings, you may have to "enable editing" in order to make the changes suggested by the exercise.

Pharmacokinetic variables on the worksheet are preset for a dog that has received phenobarbital for 2 weeks (Simulation #1) and that same dog after receiving phenobarbital for 90 days (Simulation #2). Also note the slight effect of enzyme induction on the fraction of an oral dose that's absorbed (F is lower).

Target concentrations

Manipulate parameters


Calculated values

Steady-State Concentrations (for repeated doses during therapy).



Questions (Key)

  1. What physiologic and biochemical change or changes result in increased hepatic clearance associated with enzyme induction?
  2. What physiologic and biochemical change or changes result in decreased hepatic clearance associated with hepatic failure?
  3. Does the change in the fraction of an oral dose absorbed add to the effect of altered clearance or does it counter the effect?
  4. For which of the following dogs should the dosage of phenobarbital be adjusted (immediately)?
    1. A dog whose seizures are well controlled at 120 days but with a phenobarbital Cave lower than during the second week.
    2. A dog whose seizures are not well controlled during the second week and whose phenobarbital Cave is 30 μg/ml.