MUSC Scientists Discover Mutation Related to ADHD Drug Metabolism


Contact: Heather Woolwine


June 13, 2008

MUSC Scientists Discover Mutation Related to ADHD Drug Metabolism

Discovery may open door to pre-testing, has implications for other medications

CHARLESTON -- It's not unusual for scientists to focus their work in one direction, only to discover something unexpected. Researchers within the Darby Children's Research Institute at the Medical University of South Carolina (MUSC) have discovered a gene mutation directly involved in the metabolism of the most common and perhaps most known medication used to treat ADHD, methylphenidate (MPH), or Ritalin®. This research is described in full detail in the June 2008 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 and Biomedical Sciences, who along other members of the Laboratory of Drug Disposition and Pharmacogenetics and additional collaborators worked on the unfolding discovery. "When it became clear that this individual could not metabolize or deactivate the psychostimulant 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.

Imagine the relief a patient or parent of a treated child might feel, having access to advance testing to be sure that they can adequately metabolize this medication and avoid adverse effects and potential toxicity. Furthermore, pre-testing 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."

About MUSC

Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 11,000 employees, including 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $1.6 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital and a leading Institute of Psychiatry. For more information on academic information or clinical services, visit or