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Researchers find ADHD drug linked to gene mutation

Researchers at the Darby Children’s Research Institute have discovered a gene mutation that is directly involved in the metabolism of a commonly prescribed medication used to treat ADHD, methylphenidate (MPH), or Ritalin. The findings, which were discovered by accident, are reported in the June issue of the American Journal of Human Genetics.
“It was really serendipity to come across this individual with the gene mutations, as he was part of a normal volunteer study we were working on,” said John S. Markowitz, Pharm.D., associate professor in the South Carolina College of Pharmacy’s Department of Pharmaceutical & Biomedical Sciences. Markowitz and other members of the Laboratory of Drug Disposition and Pharmacogenetics worked with collaborators on the discovery. “When it became clear that this individual could not metabolize or deactivate the psycho-stimulant methylphenidate, we immediately began to wonder about his genetic makeup, and discovered that this individual had two gene mutations that had not been previously reported.”
Normally, MPH is quickly deactivated after taking a pill several times a day or through the use of time-release formulations. The carboxylesterase-1 gene (CES1) encodes for the principal liver enzyme that governs the metabolism of MPH, widely considered the “gold standard” treatment for ADHD. The discovery that individuals with a mutation in the CES1 gene has, for the first time, provided clinicians a means to pre-test individuals prior to the usual trial-and-error method used when choosing an initial ADHD medication. Currently, predicting how an individual might respond to any ADHD medication isn’t generally possible.
With this discovery, a patient or parent of a child could have advance testing to be sure if they can adequately metabolize ADHD medication and avoid adverse effects including potential toxicity. Pre-testing also could avoid the unnecessary time and expense of a failed drug trial by allowing the treating clinician to screen for the mutation and initiate a different type of drug at the outset of treatment that uses a different enzymatic pathway if the mutation is present.
“This discovery has told us a lot more beyond the MPH pharmacotherapy, and has led us to focus more closely on the wider implications the mutation itself and the CES1 enzyme produced.
Importantly, there are all kinds of other medications with representatives from almost every drug class referred to as pro-drugs, including common blood pressure medications, that require functional CES1 to metabolize those drugs into their active forms,” Markowitz said. “Without functional CES1 to activate the administered drug, there is a very real potential for individuals taking these pro-drugs to experience medication-related problems. For instance, if it seems that the dose is not having its intended effect, many clinicians would increase the dose a few times before changing medications and the inactive or less active parent drug administered may accumulate and run the risk of unanticipated toxicity for the patient.”

Friday, June 20, 2008
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