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Dangerous Drug Combinations

by Mark T. Marino, MD

Synergism. Drugs can also interact when they have the same intended effect or complementary effects. For instance, this can occur when several drugs are given to prevent blood clots from forming. Although both aspirin and warfarin (Coumadin) are intended to prevent blood from clotting inappropriately, in combination they can increase the risk of bleeding.

Rosiglitazone (Avandia) and pioglitazone (Actos) can produce edema (fluid retention). When these diabetes drugs are given in combination with insulin or metformin, the risk of edema increases. The mechanism behind this interaction is still unknown.

Specific drug interactions
This table lists common drugs used to treat diabetes as well as other drugs commonly used by people with diabetes that could potentially cause interference. The list is not meant to be comprehensive; there are other drugs used by people who have diabetes that may cause interactions. (For more comprehensive lists, see the Web sites mentioned later in the article.)

You may remember the recent recall of the statin cerivastatin (Baycol), but perhaps you haven’t heard how the drug interaction in that case relates to a diabetes drug. The triglyceride-lowering drug gemfibrozil (Lopid), an inhibitor of CYP2C8, was connected with an increased incidence of muscle breakdown (rhabdomyolysis) as well as deaths when taken with the cholesterol-lowering drug cerivastatin. The combination causes cerivastatin levels in the blood to increase by up to 600% on average because cerivastatin is usually metabolized by CYP2C8 and CYP3A4. Cerivastatin was removed from the market because of the risks.

The same mechanism appears to be occurring with the combination of repaglinide (Prandin) and gemfibrozil and with rosiglitazone and gemfibrozil. Repaglinide is usually broken down in the body by CYP2C8 and CYP3A4. Gemfibrozil’s inhibition of the CYP2C8 enzyme appears to result in increased levels of repaglinide in the blood. The levels are increased so much that on average they essentially convert the dose taken into one 800% higher. When repaglinide is given in combination with gemfibrozil and itraconazole (Sporanox, an antifungal drug and CYP3A4 inhibitor), the increase becomes even more profound (up to 1,940%). If your usual dose is a 1-milligram tablet of repaglinide, the three-drug interaction would potentially give you the same blood levels of repaglinide as if you had taken 19 tablets, an overdose rather than the intended dose. Gemfibrozil’s CYP2C8-blocking effect also seems to be behind its ability to increase levels of rosiglitazone when the two are taken together.

Why did this take so long to figure out and why was this not understood before repaglinide was put on the market? Although the U.S. Food and Drug Administration (FDA) requires new drugs to undergo studies of potential drug interactions before they can be approved, it’s difficult to test a new drug against every known drug, so a method was devised to help target the most likely interactions to study. The method that the FDA and pharmaceutical companies came to rely on is done in vitro (in test tubes) with human enzymes (cloned and expressed in cell culture). The most common human enzymes are used in these studies, and CYP2C8 is not usually one of them. It was not until very recently that this enzyme was found to be blocked by gemfibrozil. It has also not been the practice lately to do interaction studies with more than one drug at a time, even if the blocking of two or more enzymes simultaneously would have potentially significant consequences. The findings from the cerivastatin–gemfibrozil, repaglinide–gemfibrozil, and rosiglitazone–gemfibrozil interactions may spur both the FDA and drug companies to look much closer at how drug interaction studies are done.

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