Deuterated therapeutics: forensic toxicology consequences.

The toxicology community should be aware that pharmaceutical companies are developing deuterated analogues of therapeutic agents, purported to have improved margins of safety and reduced potential for drug interactions, according to a recent report (1). According to the article in Nature, companies are " snapping up intellectual property rights " on many of the modified drugs. Earlier this year, Concert Pharmaceuticals (Lexington, MA) reported the results of a phase I clinical trial of deuterated paroxetine. Paroxetine (Sertraline) was first marketed by GlaxoSmithKline in 1992. According to a study of 94 women, the deuterated drug was less susceptible to drug interactions when co-administered with another drug (dextromethorphan), also metabolized by the CYP2D6 isoenzyme. Other companies have followed suit. Auspex Pharmaceuticals (Vista, CA) completed phase I clinical trials on SD-254, a deuterated analogue of venlafaxine (Effexor), initially developed by Wyeth in 1993. According to the report, the deuterated venlafaxine had fewer side effects and a longer half life. According to their website, Auspex develops next-generation medicines with improved safety and performance and has pioneered the targeted application of deuterium chemistry to clinically validated drugs (2). Auspex has filed patent applications on hundreds of novel therapeutics based on clinically validated drugs. These include atomoxetine, duloxetine, fluoxetine, hydrocodone, ibuprofen, oxycodone, paroxetine, venlafaxine, and zolpidem, to name a few (3). for deuterium-labeled rimonabant and mosapride, respectively. They have filed over 100 patents to date and " believe that these two patents are the first of many that will be granted on compounds derived from [their] deuterium chemistry platform " (4). The press release announcing the two patents states that " Concert's approach leverages known activity and safety of existing drugs to reduce time, risk and expense to drug research and development ". According to a June 2009 news report and press release, Concert Pharmaceuticals, Inc. and GlaxoSmithKline will collaborate to develop and commercialize deuterated drugs in a deal worth $1 billion (5,6). The article in Nature speculates that just as pharmaceutical companies often include active isomers and specify chirality in their patents, they may also include deuterated analogues to protect their intellectual property and drug discover costs (1). Proponents of this new approach explain the difference in pharmacological properties that are due to deuterium's ability to form stronger bonds than hydrogen. Although toxicologists and the scientific community at large support and encourage research to develop safer and more effective drugs, we must be mindful of …