Which drugs have clinically significant interactions with phenobarbital in dogs and how should I adjust dosing?

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Fluconazole is the highest-priority interaction: it inhibits cytochrome P450 enzymes and causes clinically significant phenobarbital (PB) accumulation, producing sedation, ataxia, and elevated liver enzymes consistent with PB toxicity. A baseline serum PB concentration should be obtained before starting fluconazole, with reassessment 7–10 days after initiation and close monitoring for toxicity signs; PB dose reduction is warranted if concentrations rise above the therapeutic target of 15–35 mcg/mL (trough) in dogs.16 Phenobarbital induces hepatic CYP enzymes and accelerates the clearance of levetiracetam (LEV), requiring substantially higher LEV doses to achieve therapeutic concentrations. Using the relationship quantified in epileptic dogs — serum LEV concentration = −1.92 × PB oral dose + 0.03 × LEV oral dose + 26.96 — a dog receiving a mean PB dose of 7 mg/kg/day would require a starting LEV dose of approximately 216 mg/kg/day (72 mg/kg q8h) to achieve a serum concentration of at least 20 mcg/mL.11 The extended-release LEV formulation shows the same interaction, with PB co-administration increasing apparent oral clearance and volume of distribution while reducing peak concentration and area under the curve.7 Dogs on PB receiving LEV should be started at higher-than-standard doses, with dose escalation guided by clinical response. Cannabidiol (CBD) does not produce a pharmacokinetic interaction with PB at a dose of 10 mg/kg — no dose adjustment of either drug is needed based on PK data alone. No significant differences in PB pharmacokinetic variables were found when PB (4 mg/kg) was administered with or without CBD (10 mg/kg).2 However, chronic CBD administration at 10–20 mg/kg/day causes elevated alkaline phosphatase (ALP) in dogs (reported range 301–978 U/L) and hyporexia, and at higher doses in combination with other antiseizure medications, elevations in alanine transferase (ALT) and bile acid concentrations have been observed, raising concern for hepatic inju