A majority of clinically significant drug interactions happen due to interactions in metabolism. A primary enzyme involved in hepatic drug metabolism is the cytochrome oxidase system, also known as CYPs.
There are many types of cytochrome P450 enzymes present in mammalian species. These membrane-bound enzymes are expressed in the endoplasmic reticulum of the liver, kidney, brain, adrenal, and other organs (1).
CYPs perform oxidation or reduction reactions on substances that are foreign to the body, effectively inactivating chemicals and making them more polar, or water soluble, to be eliminated from the system via excretion.
We can take advantage of some CYP interactions. One example of this is using ketoconazole to lower the dose of cyclosporine needed as the CYP interaction raises cyclosporine plasma levels. We also have to be careful of some CYP interactions because they decrease plasma levels of drugs or lead to the creation of toxic metabolites.
| Common CYP Interactions in Dogs (1) | ||
| Drug | CYP | Effect |
| Ketoconazole | CYP3A26 | Decreases metabolism (clearance) of cyclosporine leading to increased plasma cyclosporine concentrations |
| Fluoroquinolones | CYP1A2 (canine ortholog) | Increased serum theophylline concentrations |
| Chloramphenicol | CYP2B11 | Prolonged elimination half-life and prolonged sedation with phenobarbital, phenytoin, pentobarbital, propofol |
| Phenobarbital | CYP3A12 | Induction of CYP leading to decreased digoxin elimination half-life |
| Common CYP Interactions in Cats (1) | ||
| Cyclosporine | CYP3A (feline ortholog) | Decreases metabolism (clearance) of cyclosporine leading to increased plasma cyclosporine concentrations |
CYPs can perform the following actions:
- Convert drugs into inactive metabolites
- Bioactivate prodrugs into active drugs
- Generate reactive toxic metabolites
- Cause drug interactions (when two drugs have affinity for the same CYP)
- Generate a reactive metabolite that binds irreversibly to a CYP, terminating its function
- Bind to specific nuclear receptors, inducing a CYP and promoting its function
By Alex Gochenauer, PharmD, DICVP, FSVHP, FACA, Pharmacy Director
References
- Trepanier LA. Cytochrome P450 and its role in veterinary drug interactions. Vet Clin North Am Small Anim Pract. 2006 Sep;36(5):975-85, v. doi: 10.1016/j.cvsm.2006.05.003. PMID: 16984823.
