FAQs About Drug Interactions in Veterinary Dermatology

Veterinarians often prescribe multiple drugs concurrently to improve patient outcomes, whether managing a single condition requiring combination therapy or addressing multiple coexisting diseases. For veterinary dermatology and otology cases, a multimodal approach is widely recommended, particularly for managing allergic skin diseases. A multimodal approach provides a more comprehensive and effective treatment strategy and underscores the value of understanding drug interactions. This article focuses on clinically significant drug-drug and drug-food interactions, emphasizing those both outside the patient (in vitro) and inside the patient (in vivo). In vitro interactions—arising from the mixing or compounding of drugs—are often overlooked due to limited awareness of potential chemical incompatibilities. In contrast, in vivo interactions typically garner more attention from clinicians when multiple drugs are prescribed.

For in vitro interactions, which drug interactions do I need to be aware of when compounding ear medications?

Topical therapy is a cornerstone of otitis externa management. Although numerous commercial products are readily available for managing ear conditions, antibiotics, antifungals, corticosteroids, and ear cleaners are commonly compounded to tackle bacterial and fungal infections, manage inflammation, and streamline treatment protocols. However, some drugs may be incompatible with certain compounds or sensitive to pH changes; improper mixing can inactivate ingredients, thus compromising effectiveness.

Fluoroquinolones, for instance, are known to chelate with multivalent cations, such as aluminum, calcium, magnesium, iron, and zinc, which can reduce their effectiveness. As another example, aminoglycosides are more stable in acidic formulations in vitro, although their antibacterial activity may be reduced in acidic in vivo environments, such as purulent discharge. Consequently, when considering such formulations, referring to studies of the chemical stability of compounded drugs is highly recommended.

Various studies have assessed the chemical stability of compounded drugs (e.g., enrofloxacin, amikacin, ceftazidime, silver sulfadiazine, dexamethasone) at different concentrations and with different vehicles.^1-6 When compounding these drugs, clinicians are encouraged to check the summarized data (TABLE 1) and stay updated on newly available data in order to optimize outcomes. Note that these studies are conducted in vitro and may not fully reflect in vivo clinical responses. The lack of clinical studies evaluating patient responses to various compounded formulations highlights the need to carefully consider individual patient factors when compounding drugs.

For in vivo interactions, which drug interactions are clinically important when multiple drugs are prescribed or given with/without food?

Cations, pH, and Food

As previously discussed, drug interactions involving cations and pH changes can also occur within the patient, with food additionally playing a significant role. Given the numerous drug-food interactions, only selected key concepts relevant to veterinary dermatology are discussed in this article.

For example, the effectiveness of fluoroquinolones and tetracyclines can be compromised by antacids and gastrointestinal protectants that contain cations. Common examples include aluminum hydroxide, magnesium hydroxide, and sucralfate. To minimize the interaction, the American College of Veterinary Internal Medicine consensus statement recommends administering antibiotics at least 2 hours before antacids when they are given concurrently.⁷

Antifungal drugs such as ketoconazole and itraconazole (capsule form) are lipid soluble and depend on gastric acidity for their dissolution and absorption; thus, it is advisable to administer these drugs with food and dietary lipids, thereby stimulating gastric acid secretion and improving dissolution.⁷ Conversely, antacids, which increase gastric pH, may hinder dissolution of antifungal drugs, and concurrent administration should be avoided. Of note, fluconazole and itraconazole (solution form) are less affected by food or pH changes than ketoconazole and itraconazole (capsule form).⁸

Isoxazolines are a new class of ectoparasiticides with high lipid solubility. Administering isoxazolines with food may improve absorption; fluralaner and lotilaner show the most pronounced effects, and others are less or not influenced.^9-11

Cytochrome P450

The hepatic cytochrome P450 (CYP) enzyme system is crucial for drug metabolism, and its induction or inhibition by certain drugs can significantly affect the effectiveness and safety of concurrently administered drugs that rely on these enzymes (TABLE 2).

For example, rifampin is a CYP inducer that accelerates the metabolism of drugs that rely on those enzymes when administered concurrently, potentially reducing their effectiveness and necessitating a dosage increase. In contrast, ketoconazole is a CYP inhibitor that affects multiple CYP enzymes,¹² slowing the metabolism of many drugs, which can lead to increased drug concentrations and a higher risk for toxicity of concurrently administered drugs. One classic example is cyclosporine, a CYP substrate that relies on CYP enzymes for metabolism. When administered with CYP inducers, its plasma concentration may decrease, potentially requiring a dosage increase. Conversely, when cyclosporine is used with CYP inhibitors, its concentration may increase, potentially necessitating a dosage reduction to avoid undesired effects.

Although CYP inducers/inhibitors have been extensively researched in human medicine, research in veterinary medicine remains limited, leading to the extrapolation of many drug interactions from human data¹³; thus, care should be taken when considering these interactions for veterinary patients.

P-glycoprotein

P-glycoprotein (P-gp), also known as a multidrug-resistance efflux pump, is a membrane-bound efflux transporter found primarily in the intestinal epithelium, blood–brain barrier, liver, and kidneys. P-gp plays a critical role in drugs that are P-gp substrates by actively pumping them out of cells. P-gp inducers enhance drug efflux, increasing clearance and potentially reducing effectiveness of many drugs, whereas P-gp inhibitors decrease efflux, slowing clearance and raising the risk for drug accumulation and toxicity (TABLE 2).

For example, rifampin and corticosteroids are P-gp inducers; ketoconazole, erythromycin, and cyclosporine are P-gp inhibitors; and ivermectin and cyclosporine are P-gp substrates. A classic example is that when ketoconazole and ivermectin are used concurrently, ketoconazole, a P-gp inhibitor, may decrease the clearance of ivermectin, a P-gp substrate, thereby elevating the risk for adverse effects. In addition, dogs with the MDR1/ABCB1 (multidrug resistance 1/adenosine triphosphate–binding cassette subfamily B member 1) gene mutation exhibit defective P-gp function, making them more susceptible to drug accumulation and toxicity. A study in the United States found that 77% of collies and 47% of Australian shepherds carry such mutant allele.¹⁴ Thus, prescribing P-gp substrates or inhibitors for patients of these breeds requires caution as impaired clearance of certain drugs may lead to accumulation at toxic levels.

Are any drug interactions advantageous?

In addition to the benefits of administering isoxazolines and certain azoles (ketoconazole and itraconazole) with food, clinicians can optimize therapy by also strategically leveraging some drug-drug and drug-food interactions to optimize therapy.

For example, cyclosporine is an immunomodulatory drug widely used to treat canine atopic dermatitis as well as autoimmune and immune-mediated dermatologic conditions. However, its high cost can limit long-term use. A cost-saving strategy involves using ketoconazole, a CYP inhibitor, to slow the metabolism of cyclosporine, a CYP substrate, thereby reducing the dosage needed. One study demonstrated that dogs receiving 2.5 mg/kg ketoconazole concurrently with 2.5 mg/kg cyclosporine had blood and skin concentrations of cyclosporine similar to those of dogs receiving 5 mg/kg cyclosporine alone, the standard dose for canine atopic dermatitis treatment.¹⁵ Taking advantage of the interaction can decrease the cost of cyclosporine by up to 50%, offering a more affordable treatment option for clients facing financial constraints. However, regular monitoring of liver enzymes may be necessary, which could add costs.

Another strategy for optimizing cyclosporine therapy involves its interaction with temperature and food. Gastrointestinal upset, particularly vomiting, is a common adverse effect of cyclosporine, and freezing the capsules has been suggested anecdotally to help mitigate the issue. One study found that storing cyclosporine at − 20 °C (− 4 °F) for approximately 1 month does not affect its chemical stability or pharmacokinetics.¹⁶ Another anecdotal recommendation is to administer cyclosporine with food. Although this approach can decrease bioavailability and increase pharmacokinetic variability,^17,18 it does not seem to affect clinical response.¹⁹ Therefore, clinicians may take advantage of the interactions with temperature and food to improve patient tolerance.

Summary

Understanding drug-drug and drug-food interactions is crucial for veterinarians working with dermatologic and otic cases. Clinicians should be mindful of both in vivo and in vitro interactions as they can influence drug effectiveness, safety, and treatment success. Although some interactions may lead to adverse effects, others can enhance absorption, prolong drug activity, or lower costs. By effectively recognizing and managing drug interactions, veterinarians can improve treatment outcomes while ensuring patient safety.