Pharmacokinetic drug interactions, either as drug-to-drug or drug-to-food, have been repeatedly identified as one of many critical factors which influence the practice of modern medicine. One source of drug interactions is associated with the cytochrome P450 (CYP450) system. This is a family of isoenzymes responsible for the biotransformation and metabolism of many drugs and chemicals the body is exposed to. Comprehensive understanding of the CYP450 system and its roles in drug interactions assists health professionals identify and minimise the impact of drug issues concerning drug toxicities, variability of therapeutic effect, and adverse drug reactions.
The Role of Cytochrome P450 Enzymes in Metabolism
CYP450 enzymes play a range of important physiological roles; including the synthesis of cholesterol and its derivatives such as steroids, clearance of foreign chemicals, and drug metabolism. During drug metabolism, fat-soluble substances are biotransformed or chemically modified into more water soluble forms so they can be readily cleared from the system via bodily fluids, such as urine.
Biotransformation carried out by CYP450 enzymes is mainly via oxidation, which predominantly takes place in hepatic tissue and partly in extra-hepatic organs such as the small intestine, lungs, placenta, and kidneys.
It has been found that more than fifty CYP450 enzyme subclasses exist, and 90% of drugs are metabolised by enzymes from the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 subclasses. Each of the enzyme subclasses have selective binding affinity specific to substrates with very particular molecular structures. Together, the CYP450 enzymes ‘super-family’ contribute to the body’s ability to metabolise a range of chemicals of different shapes and sizes.
CYP450 enzymes are usually under the influence of different regulatory mechanisms. Through these biochemical processes, CYP450 enzyme activities can be induced or inhibited by specific chemical mediators, including endogenous hepatic factors and exogenous factors such as components of medicines or food.
Drug interactions may occur when drug and food components bind to these CYP450 enzymes and change their capacity to metabolise another drug. Alternatively, drug interactions involving CYP450 enzymes also occur when the exogenous components compete with another drug for the same binding site on the enzyme, and subsequently displace and exclude it from the metabolism process. This leaves the displaced drug being ineffectively cleared, and accumulating within the body.
Implication on Drug Interaction
As drugs and food components are known to induce, inhibit, or displace other drugs from binding to an enzyme; it is this physicochemical characteristic which classifies them in literature as either: an enzyme “inducer”, “inhibitor”, or “substrate”.
For example; in the drug interaction between atorvastatin and erythromycin, erythromycin acts as a potent inhibitor of the CYP3A4 enzyme which metabolises atorvastatin. As
a result, it causes elevation of the atorvastatin plasma concentration and consequently in and myopathy.
On the other hand are instances such as where St. John’s wort interacts with warfarin. As warfarin is metabolised predominantly by the CYP2C9 enzyme, St. John’s wort’s inducing effect on this enzyme accelerates the elimination of warfarin, to reduce the anticoagulant blood level and thus increases the risk of thrombosis.
The mechanism associated with each drug interaction, however, is not always straightforward and the clinical implication can vary significantly depending on the influence of many factors related to the drug, patient, and method of administration. For example, sertraline is known to be a mild inhibitor of CYP2D6 at a dose of 50mg, but it can become a potent inhibitor at doses reaching 200mg, and inhibitory effects usually occur immediately.
Additionally, drug metabolism via CYP450 can vary between different patient ethnic groups, where these enzymes are expressed at different levels according to the genetic makeup of each person, known as polymorphism. Each individual inherits copies of gene encoding for enzymes with varying levels of activity, where they can be “poor metabolisers” (reduced activity), “extensive metabolisers” (normal enzyme activity), or “ultra-rapid metabolisers” (increased activity). Polymorphism in CYP450 enzymes highlights the need for consideration of dose adjustment among different patient groups according to drug response, and suggests the need for genotype testing in future clinical practice to prevent adverse drug effects, or to help identify poor responders.
CYP3A4 and Strong CYP Enzyme Inducer and Inhibitor
Amongst all the CYP450 enzymes subclasses, CYP3A4 is the most abundant CYP enzyme in the body, accounting for 30-40% of the total hepatic CYP content, and is involved in metabolism of numerous drug substrates, of which many have a narrow therapeutic index. Therefore, CYP3A4 is the most common CYP enzyme mentioned in literature regarding drug interactions.
To date, many drugs have been recognised for their effects on particular CYP450 enzymes. Itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice have been reported to cause clinically significant drug interaction due to their strong inhibitory activities on CYP3A4. If co-administered with other CYP3A4 substrates, which have narrow therapeutic windows and potentially life threatening adverse effects, such drug interaction could result in therapeutic crises.
A list of the most clinically significant drugs that affect, or are affected by, CYP450 enzymes and their varying potency, are readily accessed in literature such as the Australian Medicines Handbook.
Apart from drug-to-drug interaction, certain foods including fruits, vegetables, herbs, spices, and teas have been reported to have the ability to affect the activity of CYP450 enzymes. Grapefruit juice is an example of a food-to-drug interaction due to its strong inhibitory effect on the CYP3A4 enzyme, which also metabolises many drugs such as cyclosporin, felodipine and the statins. Other interactions of a similar mechanism include St. John’s wort with cyclosporin and indinavir, or cyclosporin with red wine.
Implication for Prescribing and Therapeutic Monitoring in Practice
As the general population ages and acquires co-morbidities; multiple-drug regimen, or polypharmacy, becomes an inevitable element of existing and future medicinal practice. It is crucial for health professionals to be aware of possible drug interactions and their clinical implication in multiple-drug therapy, and in particular for drugs with a narrow therapeutic window.
Although elimination of the offending agent is the ideal solution to any interaction, this is not always possible. Other appropriate interventions which should be considered include prescribing safe drug combinations, slowly titrating to a response related dose, or close therapeutic monitoring of drug levels and potential adverse reactions.
- Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000 Jan; 38(1): 41–57.
- Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metabolism and transport. Clin Pharmacokinet. 2003; 42(13): 1071–88.
- Lynch T, Price A. The effect of cytochrome p450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007 Aug 1; 76(3): 391–6.
- Ogu CC, Maxa JL. Drug interactions due to cytochrome P450. Proc (Bayl Univ Med Cent). 2000 Oct; 13(4): 421–3.