Drug Interactions: A Matter for Enzymes
What is a drug Interaction?
A drug interaction is the change of one drug’s effect on the body, or its amount in the body, by another taken drug. The effects usually result in an increase or decrease of the effects of one or both of the drugs.
With the use of medications increasing, particularly with the development of new medications that can treat conditions that previously had no therapeutic medications available, there are mounting concerns about drug-to-drug interactions. The chance of drug interactions rises steeply with the number of drugs a patient is taking. For instance, going from taking two drugs to taking four drugs more than doubles the risk of drug interactions. It is not possible to evaluate or predict all of the drug interactions that may be associated with taking medications since the combinations of drugs that can be used by the entire population are seemingly infinite. Testing for drug interactions in clinical trials is not only expensive, but also difficult to conduct, and the data gathered has limited usefulness in predicting what the significance of the interaction might be on individual patients. For these reasons, not much testing is done. Often healthcare professionals rely on putting together the known characteristics of different drugs, their effects on the body and its systems and organs in determining the likelihood of a drug interaction.
Why do drug interactions occur?
Drug interactions can occur through several mechanisms. It is how the interaction occurs which helps determine the possible significance of the interaction and the likelihood it will have any noticeable effect. Some drug interactions are very minor, and although there is an interaction and one or more of the drugs being taken can be affected, it may be insignificant and causes no apparent harm or clinically significant change to how the drug works.
However, some drug combinations may cause one drug to be more or less active by altering the body’s response to the drug, causing the body to be more sensitive or resistant to drug effects. Drugs can interfere with one another directly by binding to each other resulting in a complex that is inactive once bound together, or rendered not absorbable by the body. For instance, an antibiotic called ciprofloxacin (Cipro®) can bind to aluminum, calcium, or magnesium that are the main active ingredients in many antacids. This complex that is formed cannot be absorbed by the body and results in less of the antibiotic getting into the body to treat an infection. Concentrations of ciprofloxacin in the blood have been reported to decrease by 14-50% as a result of taking the drug with an antacid and there have been reports of reducing ciprofloxacin levels as much as 90%. The large range is dependent upon a number of variables, such as the timing between taking the drug and antacid, the amount of each being taken, and when a meal was consumed in relation to the dosing times. There can be varied responses in different individuals, even if all other conditions remain the same. The reasons for this are not well known, but may be related to how each individual’s body deals with drugs based on their genetic background.
Therefore, because there is so much variability, it is not possible to predict the exact effect of many drug interactions. Avoiding the interaction all together would be the best approach in situations where it is feasible. It is known that if an antacid is taken at least two hours apart from the ciprofloxacin, then an interaction will be prevented from occurring. The separation in time helps to keep the drug and antacid from mixing together by allowing enough time for each drug to move to a separate area in the digestive system.
Enzymes
Besides predictable drug-to-drug interactions such as chemical binding, which are known from the characteristics of the chemicals, there are drug interactions that arise due to the effect of one or more drugs on the body, and how it deals with these drugs. One important source of interaction stems from a family of enzymes that is important for the body’s ability to metabolize or “get rid of” certain drugs. The Cytochrome p450 oxygenases or p450 enzyme system is responsible for metabolizing many drugs and removing or neutralizing toxins in our body. This enzyme system, discovered in 1958, was not talked about much outside of the research world until the 1990s.
Today, there is more and more research and discussion of the p450 enzyme system and much interest in its specific effects. The term p450 enzyme system refers to the entire collection of these enzymes. The individual enzymes are further classified with a code system made up of letters and numbers (e.g. 3A4). There are over 700 different kinds of p450 enzymes referred to as isoenzymes found in animals, plants, fungi, and bacteria. Humans have about 50 different isoenzymes that are known so far. Differentiating these enzymes requires many laboratory and chemical tests. Each person has a unique collection of these enzymes based on their genetic make-up. What makes this system so important is that it is used in breaking up and detoxifying substances and chemicals we ingest, mostly in food, as well drugs.
Since different species of animals have a different collection of p450 enzymes tailored to the animals’ environment and diet, animal testing of drugs is not reliable in determining human drug interactions associated with these enzymes. Many drugs have been reported to either inhibit or slow the function of specific isoenzymes to some degree, while other drugs may induce or make the isoenzyme metabolize faster. This can have a dramatic impact on the body, especially if a person is taking one drug that inhibits the enzyme that is mainly responsible for metabolizing another drug taken at the same time.
There is heightened interest in this enzyme system because people with different ethnic decent and genetic background seem to have a different collection of p450 enzymes as well as differences in how fast these enzymes work. For example, it has been determined that 22% of Japanese people are missing the p450 isoenzyme named 2C19. Drugs such as diazepam, (known commonly as Valium® from the first brand name), which is a sedative; and omeprazole (Losec®), a stomach acid suppressant agent; are mainly metabolized by the 2C19 isoenzyme. Those without the enzyme would require lower doses of these drugs for similar effects, compared to those with normal levels of these enzymes. Where the 2C19 isoenzyme leaves off, other enzymes in this system try to pick up the slack and will metabolize these drugs, but to a slower degree than the 2C19.
Poor and Extensive Metabolizers
People are also categorized sometimes into 2 groups based on the activity of their p450 enzyme system: “poor” metabolizers, who have dysfunctional or inactive enzymes and “extensive” metabolizers, who have enzymes showing normal activity. Poor metabolizers account for 3% to 7% of Caucasians, and the frequency varies between different ethnic groups. The variation in metabolic activity has a range of 10 to 100-fold difference between poor and extensive metabolizers. This may help explain why some drugs at a standard dose have more profound effects on some people than others.
In addition to all the variations in the type, abundance, and activity of isoenzymes in different people, there are drugs that are preferentially metabolized by a select few or one isoenzyme. Drugs that tie up or slow down an isoenzyme are referred to as “inhibitors” of that isoenzyme. There are drugs that cause specific isoenzymes to work faster or cause more of these enzymes to be produced resulting in an increase in metabolic activity of the isoenzyme. These drugs are referred to as “inducers”. Furthermore, there are drugs that neither inhibit nor induce any isoenzyme, but require an isoenzyme to metabolize it; these drugs are termed “substrates” of that isoenzyme. As would be expected, inducer drugs given together with substrate drugs (both involving the same isoenzyme) will lead to a decreased effect and amount of the substrate drug in the body. Whereas inhibitor drugs given together with a substrate drug involving the same isoenzyme will lead to an increased effect of the substrate drug as it builds up and is not being metabolized as it normally would be.
Major Interactions – Seldane®
A notable example of such an interaction entered the media in Canada in 1992, when a large number of serious cardiac events and some deaths came to light. These alarming events were associated with an interaction between terfenadine (at the time known commonly as Seldane® from the initial brand name), which is an over-the-counter antihistamine; and a growing list of drugs that inhibit the p450 isoenzyme 3A4. Prior to 1992, terfenadine and many other over the counter products containing terfenadine could be bought at the pharmacy without any discussion with the pharmacist and without a prescription. In 1992, the potential was identified for interactions that could result in these rare occurrences of serious cardiac problems. At that time, all products containing terfenadine were reclassified and were only available from behind the counter after a discussion with a pharmacist. The main route of eliminating terfenadine from the body is via the activity of the p450 isoenzyme 3A4. Drugs inhibiting the activity of this isoenzyme important for metabolizing terfenadine can result in the build-up of toxic levels of terfenadine in the body and a predisposition to cardiac problems. However, this interaction was known of; warnings were printed on the drug label and letters were sent to doctors identifying the potential problem of using terfenadine with drugs that inhibit 3A4 (particularly an antifungal drug called ketoconazole), but these actions were not enough to eliminate the occurrences of the interaction and adverse outcomes.
In 1997, terfenadine-containing products (many allergy and cold remedies) were once again reclassified due to the concern of misuse of this drug. The drug was then moved to prescription status. However, there were increasing numbers of drugs being identified as having the potential to interact with terfenadine, mainly affecting the activity of the isoenzyme 3A4, and thereby increasing the risk for the rare and serious cardiac side effects. By the end of 1999, all pharmaceutical manufacturers in Canada producing terfenadine-containing products voluntarily halted production and cancelled the license of their products containing this drug. In all, 24 products were removed from the market as a result of this concern of adverse outcomes caused by interactions. Terfenadine was introduced on the market in 1985 as Seldane® and was one of the best-selling antihistamines due to the advantage of relieving allergies without causing much sedation as many other antihistamines did at the time. However, it took almost 15 years before the dangers identified lead to its withdrawal from the drug market in Canada.
Major Interactions – Prepulsid®
Terfenadine was not the only drug withdrawn from the Canadian market because of p450 enzyme-related interactions. Recently, in August 2000, a gastrointestinal motility drug, cisapride (Prepulsid®) was removed from the market due to similar cardiac events and deaths as with terfenadine. Although the overwhelming majority of adverse cases involved known risk factors such as an interacting drug, 1% of the cases did not have an identifiable cause. In Canada, there have been 22 cases of serious cardiac arrhythmias (irregular heart rhythms), and 6 of the cases resulted in death since the introduction of the drug in 1990. Cisapride, like terfenadine, is a substrate for the p450 isoenzyme 3A4.
Potential Danger of Grapefruit
Many people may take drugs or even foods containing substances that are inhibitors of the isoenzyme 3A4, including grapefruit juice. It is now well recognized that grapefruit juice can inhibit the metabolism of many drugs that are substrates for isoenzymes 3A3, 3A4 and 1A2. Many people who enjoy grapefruit juice may unknowingly be building up the levels of these substrate drugs in their body. Therefore, it is important to check with your doctor or pharmacist about potentials of drug interactions if you drink grapefruit juice or eat grapefruits regularly. It is unclear how much of the fruit or juice is enough to result in an interaction, but the more grapefruit consumed, the greater the likelihood and level of drug interaction.
Conclusion
Drugs introduced to the market today are screened to determine which isoenzymes are responsible for its metabolism and whether it may be an inhibitor or inducer of important isoenzymes. However, since not every isoenzyme can be tested against a drug, some minor isoenzyme associations can be missed. Drugs can be metabolized exclusively by one isoenzyme or by several. The degree of metabolism each isoenzyme is responsible for can vary. So, not only can one drug be the substrate for one or more isoenzymes, but also each isoenzyme may be more or less efficient at metabolizing the drug. This is in addition to the possibility of the drug possessing either an inhibitory effect or an inducing effect to one or more isoenzymes.
Because of this important relationship between drug metabolism, genetics, and effect of drugs on the body, a discipline devoted to the study of these issues has been created, Pharmacogenetics. This is the study of genetically inherited conditions that affect the way drugs act on the body and/or change the way the body acts on drugs.
Drug interactions are a matter of enzyme presence and activity altered by the presence of drugs. Since there are so many variables associated with the effect of drugs on the body and the limited information available with respect to drug interaction studies of different drug combinations, we must exercise caution when there is any potential for drug interactions, or when there is a suspected drug interaction based on characteristics that are known about the drugs. Avoiding a possible drug interaction is the safest approach, but not always an option.
It is essential that your doctor and pharmacist are aware of all medications you are taking, even if they are non-prescription or herbal products. Grapefruit deserves special mention due to the unique effects of its components on the body’s ability to metabolize certain drugs.