Polypharmacy is defined as the use of multiple medications, generally by older patients. Nearly 50% of older adults–aged 65 and older–are taking one or multiple medications they have no medical need for.¹ Understanding how drugs interact with one another is something you might assume would be well studied and understood given the potential for negative side effects. Unfortunately, you would be incorrect and much is still unknown with regards to the interactions. In research published in the December issue of Drug Metabolism and Disposition, a Kalamazoo College professor and three student co-authors decided to shed light on the very core mechanisms at the heart of this problem.

Professor Laura Furge is the Roger F. and Harriet G. Varney Professor of Chemistry at Kalamazoo College. As senior author, she led a team of Kalamazoo research students—Amanda Bolles, Erran Briggs, and Rina Fujiwara. Their work, titled “Mechanism-based Inactivation of Human Cytochrome P450 3A4 by Two Piperazine-containing Compounds,” explores the specific enzymes responsible for the metabolism of nearly 60% of known drugs. In a press release from the college, Furge explained that “multiple-drug regimens can lead to unwanted side effects, including drug-induced inhibition of the very enzymes responsible for the metabolism and clearance of other co-administered drugs. This paper adds in understanding of how certain classes of drugs may cause this type of unfavorable medical event. New insights will hopefully lead to better prevention in the future.”

So why are doctors prescribing drugs when potential interactions are not well understood? Drug-drug interactions are often not studied prior to administration for a variety of reasons, financial considerations and time constraints being the most prevalent. “In an ideal world, we would start each medication 1 at a time, determine the side effects of each medication as it is initiated, and then be able to say with some certainty what side effects were caused by which medication,” explains Medscape. “Unfortunately, in the real world, often acutely ill patients and time constraints preclude being able to leisurely begin polypharmacy. Too often, we start more than 1 medication at once and then we are left with the task of trying to figure out how to deal with side effects that may come from multiple medications or multiple combinations of medications.”

This dilemma is exacerbated by the incredible increase in usage of psychopharmaceuticals (antidepressants) by younger demographics in recent years. “Antidepressants were the third most common prescription drug taken by Americans of all ages in 2005–2008 and the most frequently used by persons aged 18–44 years. From 1988–1994 through 2005–2008, the rate of antidepressant use in the United States among all ages increased nearly 400%” Additionally, “Eleven percent of Americans aged 12 years and over take antidepressant medication.” Research shows a “higher prevalence of side-effects was seen in polypharmacy of antipsychotics.”

In 2005, an important paper was published regarding CYP3A4 that concluded that “the clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.”

Furge’s research aims to accomplish just that. Better understanding of the core mechanisms responsible for drug-drug interactions will open new avenues of research to better assist a growing pharmaceutical industry facing real world constraints.

Photo Credit: Kalamazoo College

¹Notes: Lead-in paragraph data from http://www.ncbi.nlm.nih.gov/pubmed/24073682.