How non-interacting drugs interact
When planning dual drug therapy clinical studies, medical experts devote considerable effort to understanding the nature and severity of any possible drug interactions. These efforts largely focus on the potential for each drug to alter the expression of metabolic enzymes and transporters involved in the elimination of the other drug. When no change in the expression of either of these is detected, it is generally accepted that interaction of the two drugs is unlikely. Little consideration is given to how the body’s physiological response to one drug may affect the in vivo performance of the other. Unfortunately, interactions do sometimes occur for drug combinations that were believed to be non-interacting and these unexpected interactions can have negative consequences for patients and for clinical study outcomes. Two common physiological reactions are responsible for most of these unexpected drug interactions. They are:
Slowing of the gastric emptying rate
Prolonged gastric retention, followed by rapid expulsion of gastric contents to the colon
The fasted state gastric emptying rate varies a great deal between individuals but is relatively constant, on a day-to-day basis, within individuals. However, some drugs cause the stomach to empty more slowly than it would normally do. A drug that induces slower gastric emptying may have a profound effect on the bioavailability of a second drug which would ordinarily exit the stomach quickly. For example, if the second drug is a substrate for intestinal efflux transporters, it may exhibit a large decrease in bioavailability when dosed in combination with a drug that slows gastric emptying. In this case, the expression of intestinal efflux transporters is unchanged but slow gastric emptying results in low intestinal drug concentration, which allows transporters to eliminate the drug more efficiently.
The absorption of some drugs is limited to the upper small intestine and these may exhibit a large increase in bioavailability when dosed in combination with a drug that slows the gastric emptying rate. This scenario is likely when drug absorption in the upper small intestine is limited to only a few milligrams per hour. When the slowly absorbing drug exits the stomach quickly, the opportunity for drug absorption is brief and bioavailability is low. When such a drug is dosed in combination with a drug that slows the gastric emptying, the slowly absorbing drug is in contact with the favorable absorption site for a longer period of time, which leads to greater cumulative absorption. Drugs which exhibit large, positive food effects should be anticipated to exhibit increased bioavailability when dosed in combination with a drug that slows gastric emptying.
Some drugs are retained in the stomach for a long period of time, then rapidly expelled to the colon. Naproxen is one drug which produces this response. In most patients, the majority of naproxen absorption is from the colon. A second drug administered in combination with a drug that induces this reaction will undergo the same fate. It will be retained in the stomach for one to three hours and then expelled to the colon as a bolus afterward. If the second drug is liable to convert to a less soluble form in the stomach, it will have ample opportunity for complete conversion. For example, sodium salt drugs can be expected to revert to the parent form of the drug. In this scenario, there is little or no opportunity for drug absorption in the small intestine and the second drug’s bioavailability depends on its ability to be absorbed in the colon.
For dual therapy clinical studies, a thorough understanding of the in vivo absorption process for drugs dosed separately is necessary in order to anticipate how they will perform when administered together. Advance knowledge of an expected physiological drug interaction may lead to effective risk management plans and fewer disappointments in clinical trial outcomes.