Drug interactions (focus on cytochrome P450) (Proceedings)

With the increase in concurrent use in small animal patients, drug interactions are becoming more and more likely. Polypharmacy can have a number of unintended side effects. Some drug combinations can result in decreased therapy effectiveness, while others may result in toxicity. Still others have the potential to increase therapeutic success. How do you know which drug combinations will interact?

Drug interactions continue to be identified as we better understand how these drugs are absorbed, distributed, and especially metabolised. Some terminology: the object drug is the medication affected by the interaction, and the precipitant drug is the medication responsible for the interaction. The effect may either be a pharmacokinetic (PK) effect and/or a pharmacodynamic (PD) effect. Because most of the drugs used in veterinary patients have a wide therapeutic window (concentration range that produces desired effect) and a large therapeutic index (margin of safety), drug interactions may not be observed clinically. Generally, an interaction that causes a doubling or more in plasma drug concentration has the potential for an adverse or beneficial response.

Role of Cytochrome P450 enzymes in drug metabolism

The majority of clinically significant drug interactions occur because of interactions in metabolism. One of the primary enzymes involved in hepatic drug metabolism in mammals is the cytochrome oxidase system. These enzymes are located in microsomes on the endoplasmic reticulum of hepatocytes, as well as intestinal, kidney, brain, and other cells. CYPs are involved in Phase I metabolic reactions (making lipid soluble drugs more water soluble to facilitate renal/biliary excretion). CYP enzymes catalyse the hydroxylation of hundreds of structurally diverse drugs, whose only common characteristic is high lipid solubility. Because many drugs are metabolized by CYP enzymes, anything that changes CYP numbers or function can strongly influence drug pharmacokinetics (and hence drug action).

There are many different types of cytochrome P450 enzymes in mammalian species. Each is types by family and subfamily, then given a specific number. For example, one of the most common CYP enzymes in humans is CYP3A4 (family 3, subfamily A). The enzyme in dogs with a similar structure and substrate range is CYP3A12 (known as an orthologue). Researchers are beginning to elucidate the CYP enzyme family in dogs, although much work remains. Even less is known about CYP enzymes in cats.

Drug effects on CYP enzymes

There are 2 major mechanisms by which cytochrome P450 enzymes can be affected: they can be inhibited or induced.

Inhibition refers to one drug inhibiting the CYP-mediated metabolism of another drug. This will result in decreased clearance and increased concentrations of the object drug, which may increase the therapeutic effect or result in drug toxicity. Precipitant drug-induced enzyme inhibition can be reversible or irreversible. Reversible inhibition occurs when drugs compete for the same catalytic site (also called competitive inhibition) or bind to another site on the enzyme and alter enzyme binding to object drug (non-competitive inhibition). The degree of reversible inhibition depends on drug concentrations and the affinity of the enzyme for the precipitant drug. Mechanism-based inhibition is the "irreversible" inhibition of an enzyme (also called 'suicide inhibition'). Synthesis of new enzyme is necessary before activity is restored. Irreversible drug inhibition generally causes a longer-term change in drug clearance, and therefore is more likely to result in drug toxicity.

Example of CYP inhibition: Ketoconazole inhibits CYP enzymes in dogs. This will decrease the metabolism (clearance) of cyclosporine and lead to increased plasma cyclosporine concentrations. Some practitioners used this drug interaction creatively—they would administer ketoconzaole to large dogs receiving cyclosporine concurrently (like German Shepherds for treatment of perianal fistulas). This way they could lower the dose of expensive cyclosporine! Because ketoconazole isn't exactly an innocuous drug, and the resulting cyclosporine pharmacokinetics aren't conclusively known, this practice isn't generally recommended. As a side note, cyclosporine is also transported by P-glycoprotein in the intestines and liver, and ketoconazole may inhibit this protein as well. There is a large overlap between CYP and P-gp subtrates, and some compounds will inhibit/induce both proteins.

Other examples of CYP inhibition in dogs include:

• Fluoroquinolones may inhibit the clearance of the bronchodilator theophylline, leading to increased theophylline concentrations and signs of methylxanthine toxicity.

• Cimetidine inhibits multiple CYP enzymes, and can inhibit the clearance of β-blockers (atenalol, sotalol, propanolol), theophylline, cyclosporine, chloramphenicol, and many others.

• Chloramphenicol inhibits the metabolism of phenobarbital, phenytoin, and propofol.

• Bergamottin, a constituent of grapefruit juice, has been shown to irreversibly inhibit CYP3A4 in people. When grapefruit juice was given to beagles along with praziquantel, increased plasma praziquantel Cmax and AUC were observed compared to control dogs (likely because of decreased clearance through CYP inhibition). Bergamottin will also increase plasma concentrations of cyclosporine and diazepam.

• Erythromycin, phenobarbitol, and corticosteroids such as dexamethasone & prednisolone can cause inhibit CYP-mediated metabolism.

Induction: Many precipitant drugs are capable of inducing CYP enzyme quantities. This occurs when a molecule binds to the promoter region of the CYP gene, causing increased transcription of the DNA coding for the enzyme. More CYP enzyme will increase the rate of metabolism and hepatic clearance of concurrently administered drugs, typically resulting in a decreased pharmacological effect. Enzyme induction typically occurs slowly, requiring several weeks to reach maximum effect. Induction is accompanied by increased hepatic RNA and protein synthesis and increased hepatic weight. Enzyme induction is important in the pathogenesis of hepatotoxicity and therapeutic failure of many drugs.

Example: Phenobarbital is a potent enzyme inducer, known for hepatotoxicity and for inducing its own metabolism. It can induce CYP3A12 in dogs, which is also responsible for the metabolism of benzodiazepines.

Other examples of CYP induction in dogs:

• Rifampin is one of the most potent inducers.

• Omeprazole (proton pump inhibitor, used to treat gastric ulcers)

• Griseofulvin

Summary

For compounds that both inhibit and induce CYPs (such as phenobarb), predicting the net effect in your patient is difficult. Therapeutic drug monitoring is particularly valuable in such cases. However, TDM is not available for most veterinary drugs, and the cost is prohibitive in some cases. As we better characterize the specific metabolic enzymes involved for veterinary drugs, further refinements of dosing schedules is likely. However, the best advice for clinicians is simply to be aware of potential drug interactions in your patients. Pay attention to how the drugs you prescribe are metabolized, and be careful any time you administer more than one drug to a patient.

References

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Dowling, PM. Case presentations: Managing drug interactions. 26th ACVIM Forum Proceedings; 2008; 61-63.

Giorgi M, Meucci V, Vaccaro E, et al. Effects of liquid and freeze-dried grapefruit juice on the pharmacokinetics of praziquantel and its metabolite 4'-hydroxy praziquantel in beagle dogs. Pharmacol Res. 2003; 47(1):87-92.

Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2006; 2(6):875-894.

Shah SS, et al. Characterization of cytochrome P450-mediated drug metabolism in cats. J vet Pharmacol Therap. 2007; 30:422-428.

Patricelli AJ, et al. Cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs. JAVMA 2002; 220(7):1009-1016.

Aidasani D, et al. In vitro drug-drug interaction screens for canine veterinary medicines: Evaluation of cytochrome P450 reversible inhibition. Drug Metab Dipos. 2008; 36(8): 1512-1518.

Shah SS, et al. Inhibitory effects of ketoconazole, cimetidine and erythromycin on hepatic CYP3A activities in cats. J Vet Med Sci. 2009; 71(9):1151-9.