Drug interactions occur when a medication’s effects are altered by the presence of another drug, certain foods, or underlying disease states. These interactions can lead to unexpected adverse effects, increased toxicity, or changes in drug efficacy—either an enhancement or reduction of the intended effect.
Below is a refresher on some commonly encountered interactions in clinical practice. This is not intended to include all possible drug interactions. Please refer to appropriate sources for a comprehensive list of actual and potential interactions.
Ketoconazole
Ketoconazole is a potent inhibitor of several cytochrome P450 (CYP450) enzymes in dogs andCYP3A in cats. It also inhibits P-glycoprotein. As a result, ketoconazole can increase the concentrations of many concurrently administered medications, including ivermectin, cyclosporine, cisapride, and digoxin. It is especially important to monitor patients closely if they are on a medication that has a narrow therapeutic index, such as digoxin.
Interestingly, this interaction can be used therapeutically. In patients being treated with cyclosporine, ketoconazole can reduce cyclosporine clearance and increase blood levels, potentially allowing for a lower cyclosporine dose. Cyclosporine is primarily metabolized in the liver, most likely by CYP3A, and ketoconazole’s inhibitory effect on this enzyme can be leveraged to optimize treatment.
Phenobarbital
Phenobarbital induces many of the CYP enzymes and is a strong inducer of CYP3A and CYP2B11 in dogs. Phenobarbital dose increases may be needed in patients that are on it long-term since it increases its own clearance.
Phenobarbital also interacts with other anticonvulsants. It may increase both the efficacy and toxicity of potassium bromide. When used with levetiracetam, it can reduce the half-life of the immediate-release formulation and lower peak plasma concentrations while increasing clearance of the extended-release formulation. Additionally, phenobarbital can enhance the clearance of zonisamide.
Drugs metabolized via the CYP450 system should be carefully monitored when used alongside phenobarbital to ensure therapeutic levels and minimize adverse effects.
Fluoroquinolones
Certain medications containing divalent or trivalent cations—such as aluminum, calcium, magnesium, iron, or zinc—can bind to fluoroquinolones when given orally, preventing their absorption. This interaction extends to dietary sources, so dairy products should also be avoided when administering fluoroquinolones.
Caution
When evaluating drug interactions, it’s important to remember that metabolic pathways can vary significantly between species. This means that drug interaction data from humans or a different animal species may not directly translate to another. The nomenclature and classification may also vary, making cross-species comparisons more complex. For example, CYP enzymes such as CYP1A2, CYP2D15 (the canine analog of human CYP2D6), or CYP3A12 (in dogs) may metabolize drugs differently from their human counterparts. Ideally, species-specific references should be used when assessing potential interactions, but human references may provide some guidance to drugs of concern.
References
- Council on Family Health. (2013). Drug Interactions: What You Should Know. U.S. Food & Drug Administration. fda.gov/drugs/resources-drugs/drug-interactions-what-you-should-know
- Ogeer, J. (2015, January). Common Drug Interactions in Dogs and Cats. DVMetrics North American Companion Animal Formulary. Retrieved April 16, 2025 from vin.com/doc/?id=6875137&pid=256
- Plumb DC. Cyclosporine. app.plumbs.com/drug/b2qDVutWDRPROD. Updated May 2024. Accessed April 17, 2025.
- Plumb DC. Phenobarbital. app.plumbs.com/drug/8YXk71VSMDPROD. Updated December 2023. Accessed April 17, 2025.
- Plumb DC. Enrofloxacin. app.plumbs.com/drug/ajastQOmuUPROD. Updated March 2024. Accessed April 16, 2025.
- Trepanier, L. (2018) Top Ten Potential Drug Interactions in Dogs and Cats. Pacific Veterinary Conference 2018. Retrieved April 17, 2025 from vin.com/doc/?id=8550703
By Lauralei Fisher-Cronkhite, PharmD, DICVP, FSVHP, Clinical Staff Pharmacist
