Effects of phenobarbital treatment on 3-methylindole toxicosis in ponies

To study the role of cytochrome P-450-dependent mixed function oxidase reactions in equine 3-methylindole (3MI) toxicosis, ponies were given 20 mg of phenobarbital/kg of body weight at 72, 60, 48, 36, and 24 hours before 100 mg of oral 3MI/kg to induce cytochrome P-450 or no treatment (controls). Maximal 3MI plasma concentration was decreased and clearance was faster in phenobarbital-treated ponies. Plasma 3MI was still detectable 12 and 36 hours after dosing in phenobarbital-treated and control ponies, respectively. Phenobarbital treatment induced a distribution phase with transition from a 1-compartment to a 2-compartment extravascular model. Bronchiolitis occurred in all ponies 72 hours after 3MI, but was more severe in those treated with phenobarbital. Appearance of a distribution phase, increased total body clearance, and more severe bronchiolitis in phenobarbital-treated ponies indicated that mixed function oxidases are involved in metabolism and conversion of 3MI to a toxic metabolite.