Enzyme and plasma protein induction by multiple oral administrations of phenobarbital at a therapeutic dosage regimen in dogs.

In dogs effects of phenobarbital (PB) on hepatic cytochrome P450 (CYP) activities and on concentrations of plasma alpha 1-acid glycoprotein (AGP) were examined. Total body clearance (Cl(B)) of antipyrine and plasma AGP concentrations were monitored during oral PB treatment at a therapeutic dose for 35 days. Cl(B) of antipyrine, which reflects hepatic CYP activities, gradually increased and was maintained at about threefold concentrations compared with that before treatment, suggesting that PB induced CYP activities at a large extent even in a therapeutic dose, necessary for an antiepileptic effect. Plasma AGP concentrations also increased significantly (about fourfold). Dogs were killed at the 35th day of the PB treatment, and hepatic CYP content and enzyme kinetics of several CYPs were determined using liver microsomes. CYP content was about twofold higher than that from untreated dogs. The V(max) values for CYP1A-like activity (ethoxyresorufin O-deethylation), 2B-like activity (ethoxycoumarin O-deethylation), 2C-like activity (tolbutamide hydroxylation) and 3A-like activity (midazolam 4-hydroxylation) were higher (2-4-fold) than that in untreated dogs. In summary, a therapeutic dose of PB for antiepileptic therapy significantly induced hepatic CYPs and plasma AGP in dogs. Therefore, during antiepileptic therapy with PB, special attention must be paid to the pharmacokinetics of drugs simultaneously administered.