Interactions between therapeutic drugs potentially pose serious dangers to a patient. They often occur when one drug inhibits the enzymes that clear another drug from the patient's system. If the elimination of a drug--or its metabolic by-products--is decreased, then there may be a build-up of those substances in the patient's system, leading to toxic side-effects or drug overdose.
Drug interactions typically are identified and reported only after the problems have occurred. Information about interaction problems is collected and subsequently taken into account when doctors prescribe drugs, particularly when an "inhibiting" drug is added to a patient's existing treatment regimen.
UW pharmacy professor Philip Hansten and John Horn, member of the Board of Directors of the International Drug Interaction Foundation, are setting up a computerized database on clinical findings relating to drug interactions.
Despite a general awareness of the problem of drug interactions and widespread efforts to monitor them, the medical community has lacked a rigorous way to predict and prevent them. Traditionally, prediction has often involved administering a drug to healthy volunteers in the absence or presence of well-known "inducers" or "inhibitors" of the drug, and monitoring the subjects' physiological responses.
UW researchers are pioneering new ways to predict problems before they occur by understanding the role of specific enzymes in the molecular mechanisms of drug metabolism. The key is to understand a drug's major routes of metabolic elimination and the specific enzymes that catalyze those reactions. Enzymes called cytochromes P450 are the most important group of enzymes involved in the biotransformation of drugs. An individual's ability to metabolize drugs is a function of the types and amounts of these enzymes, which in turn vary with age, health, stress, and chemical or drug exposure. Among members of the general population, there is also a natural variability between individuals in the levels of these enzymes.
The strategy is to be able to do screening studies in vitro, that is, in the laboratory outside of the body using enzyme samples, to determine which enzyme systems are involved in metabolizing particular drugs and which substances might interfere with their metabolism.
Rene Levy, chairman of the UW pharmaceutics department, and William Trager, of the UW medicinal chemistry department, have headed a long-standing program to elucidate the molecular mechanisms of drug interactions. Over the past 20 years, Levy has focused on drugs for the treatment of epilepsy. He was named Ambassador for Epilepsy in 1989 on behalf of the International Bureau for Epilepsy and the International Leagues Against Epilepsy.
Carbamazepine is one of the main anticonvulsant drugs used to treat epilepsy patients; but a number of drugs inhibit its metabolism by cytochrome P450, sometimes causing pronounced increases in carbamazepine levels in the blood and intoxication. Certain antibiotics also interfere, including erythromycin. In laboratory studies, Levy and colleagues were able to identify the particular enzymes governing biotransformation of the drug, making it possible to predict for new drugs what interactions are likely to be critical.
Epilepsy is a complex disease, and therefore may need to be treated by a combination of drugs. Carbamazepine may, for example, be given in concert with the antiseizure agents valproic acid or valpromide. But drug interactions with those substances can cause the carbamazepine metabolites to build up. Levy and colleagues have established the mechanism by which valproic acid and valpromide inhibit a key detoxification enzyme called epoxide hydrolase. In fact, these are the first drugs known to inhibit that enzyme at concentrations commonly administered in human therapy.
Over the last 20 years, Trager's research has elucidated the biochemical characteristics of warfarin, an important drug in anticoagulant therapy. In doses that are too large, warfarin causes hemorrhage, so clinicians must administer the drug carefully and avoid drug interactions. Commercially available warfarin exists as two complementary forms that are mirror pathbreakers/graphics of each other--like a right and left glove, designated "R" and "S." That means the commercial preparation is really a mixture of two drugs. Trager and colleagues characterized the different metabolic and pharmacokinetic properties of the two warfarin forms, and discovered that the S form accounts for most of the biological effect--the S form is 5 to 6 times more potent that the R form. More recently, Trager and colleagues were the first to show that the metabolism of the active form depends on the activity of one particular cytochrome P450 enzyme. As a result, it is now possible to explain observed drug interactions and to predict when a new drug might interfere with the anticoagulant effect of warfarin.