This installment focuses on drug interactions as a consequence of metabolism by the cytochrome P450 (CYP) enzyme system. Due to the complexity of this enzyme system and the massive amount of literature available on enzymatic interactions, this article will focus on some of the major drug interactions involving a limited number of the CYP enzymes.
A patient case study and pharmaceutical care plan are included. The case study illustrates one or more drug interactions and offers the pharmacist an opportunity to identify drug interactions and develop a pharmaceutical care plan to address specific drug interaction problems. Since there are often numerous ways to resolve a problem, the pharmaceutical care plan included is one attempt at addressing the patient’s drug interaction problem(s).
One of the most important causes of preventable drug therapy problems is drug interactions (DIs). Factors contributing to DIs can be easily identified but preventing drug interactions is by far more difficult. To illustrate the quandary in which pharmacists find themselves and the complexity involved in evaluating drug interactions to determine safe drug use, the drug interaction portion of a drug monograph for a newly approved drug in the U.S. is reproduced below.
“Cevatine (name changed from original) should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with cevatine can be expected to have additive effects. Cevatine might interfere with desirable antimuscarinic effects of drugs used concomitantly. Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevatine. It should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at higher risk of adverse events. In an in vitro study, cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were not inhibited by exposure to cevatine.”
If cevatine were prescribed for a patient and you were the pharmacist involved, how would you approach determining whether or not it interacts with any of the other routine medication the patient takes? If the drug cevatine is not listed in your pharmacy’s computer drug information or drug interaction software programs, what drug information resources would you use? How would you advise a physician who asks, “Does cevatine interact with any other medication?” What strategies would you utilize to adequately prepare yourself to provide clinical information about drug interactions with cevatine?
With the increasing number of newer, complex drug compounds being developed, pharmacists, as the most readily accessible healthcare providers, are asked to bear much of the burden for detecting and preventing potentially serious drug interactions. Unfortunately, few pharmacists (and even fewer physicians) have received extensive training on the CYP metabolic enzyme system. As a result, many pharmacists primarily rely on computer software programs and/or drug information handbooks to detect drug interactions and provide an appropriate course of action to resolve them. However, given the rapid pace at which new drugs are introduced and new drug interactions are reported, these information resources rapidly become outdated, placing both patients and practitioners at risk.
National concern about drug interactions with CYP enzymes heightened in the 1990s when fatal cardiac arrhythmias were suspected with the interactions of terfenadine with erythromycin and ketoconazole.Ultimately terfenadine was withdrawn from the U.S. market. Since then, more examples of serious DIs involving CYP enzymes have been reported and the medical community has become very cautious about starting patients on new drugs that are metabolized by the CYP enzyme system. For example, the recent withdrawal of mibefradil from the U.S. market was, in part, due to its high potential to inhibit certain CYP enzymes and cause harmful drug interactions. Another example is the recently revised warnings in product labeling of the drug cisapride due to its risk of causing potentially fatal cardiac arrhythmias when combined with certain CYP enzyme inhibitors. As knowledge of the CYP enzyme system and reports of its involvement in potentially lethal DIs continue to increase, practitioners, researchers and pharmaceutical manufacturers have become concerned. The following overview of the CYP enzyme system is designed to help pharmacists become more knowledgeable about its ability to cause significant drug interactions.
The Cytochrome P450 Enzyme System
The term “cytochrome P450″ refers to a family of over 100 enzymes in the human body that modulate various physiologic functions. Although knowledge of these enzymes and their mechanism of action is growing, much about their physiologic role and function remains unknown. These enzymes were first identified in the 1950s to 1960, but specific research on them did not begin until the 1970s. Identification of their specific CYP genes using DNA cloning techniques did not begin until the mid-1980s. The first gene to be coded for a specific CYP enzyme occurred around 1990. The CYP enzyme system contains two large subgroups: steroidogenic and xenobiotic enzymes. The steroidogenic group is not involved in the metabolism of drugs. The xenobiotic group includes four major enzyme families: CYP1, CYP2, CYP3, and CYP4. These enzymes perform a number of physiologic functions but their primary role involves the metabolism of drugs.
The presence of these enzymes and their function are genetically determined. They enable humans to metabolize plant toxins and related toxic substances before the substances enter the systemic circulation and cause cell damage. Since many drugs are derived from botanical compounds and may resemble plant toxins, they are metabolized by these enzymes and at times by other biotransformation processes. Initially, a drug will have one principal CYP enzyme responsible for its metabolism, but if the drug concentration reaches a sufficient level in the body, a second enzyme will be released to continue the metabolic process. If needed, a third and fourth enzyme can become activated to complete biotransformation of a drug or substance into a polar metabolite that can be eliminated from the body in urine or feces.