Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) commonly used to treat pain, inflammation, and fever. It works by blocking the production of prostaglandins, which are substances in the body that cause pain and inflammation. While diclofenac is effective in relieving pain and reducing inflammation, it can also cause side effects. It is important to talk to your doctor about the risks and benefits of taking diclofenac before starting treatment.
Safety issues surrounding diclofenac, a commonly used pain reliever, may be linked to a poorly understood drug-metabolizing enzyme, according to recent research. The expression of this enzyme can vary up to 3,000 times from one person to another.
The findings of a study published in Clinical Pharmacology and Therapeutics, has the potential to be used to develop methods to identify individuals susceptible to severe side effects of diclofenac. These methods can also help determine safe dosing guidelines for specific demographic groups, including women, young children, and individuals of certain ethnic backgrounds.
Used to fight the pain and inflammation associated with arthritis, diclofenac was available as an over-the-counter drug in the US until 2013, when the Food and Drug Administration restricted it to prescription-only use because of the drug’s potential for heart damage. happens More than 10 million prescriptions are written for it in the US each year. It is also one of the most widely used non-steroidal anti-inflammatory drugs worldwide. This includes many countries in Asia, Africa and the Middle East that still allow over-the-counter use of diclofenac.
“The majority of patients who are using diclofenac have arthritis, and many of them are at risk for heart disease,” said senior author Bhagwat Prasad, an associate professor in the Washington State University College of Pharmacy and Pharmaceutical Sciences. “Therefore there is concern that taking diclofenac may put them at greater risk of cardiovascular events such as heart attack and stroke.”
Previous findings by the WSU team found high levels of variability in the expression of UGT2B17, an enzyme that is a known player in diclofenac metabolism. That study showed that the enzyme was present at much lower levels in women than in men, which researchers thought might explain the increased risk of heart damage seen in women taking diclofenac. They also found that the enzyme is mostly absent in children under the age of nine and found large race-based differences in the number of people lacking the gene for the enzyme, ranging from about 20% in Caucasians to about 90%. of the Japanese people.
In this new study, WSU researchers used human liver and intestinal samples with computer-based modeling to quantify the degree to which this enzyme contributes to diclofenac metabolism compared to other related enzymes. They found it to be a key player, supporting the idea that low levels of the UGT2B17 enzyme may be the cause of heart damage associated with diclofenac use.
“Nobody knew why this cardiotoxicity was occurring in some individuals,” said first author Deepak Ahir, a graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences. “Our study shows, for the first time, that UGT2B17 is important in diclofenac metabolism and suggests that differences in UGT2B17 expression make people’s response to diclofenac so variable, leading to toxicity in some while the drug doesn’t work for others.”
Ahir said his study found that this enzyme metabolizes diclofenac primarily in the gut, unlike other related enzymes that are mostly active in the liver. As a result, the effect researchers are seeing is specific to oral diclofenac tablets, which provide rapid absorption and pain relief. Just under half of the prescriptions written for the drug in the U.S. are for oral diclofenac, Prasad said.
The researchers’ findings suggest that it is possible to use genetic testing to help healthcare providers assess safety risks before prescribing diclofenac. Prasad also noted that drug regulatory authorities in countries where diclofenac is still available over the counter should consider conducting efficacy trials to determine the optimal dosage of the drug for their local market.
The WSU researchers are currently in the process of confirming their findings in a pilot clinical trial. Their next step will be to collaborate with major hospitals to study the link between diclofenac and heart damage in patients’ electronic medical records.
Reference: “Intestinal metabolism by polymorphic UGT2B17 correlates with its highly variable pharmacokinetics and safety across populations” by Deepak Ahire, Scott Hayward and Bhagwat Prasad, 12 Apr 2023, Clinical Pharmacology and Therapeutics.
DOI: 10.1002/cpt.2907
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, a component of the National Institutes of Health.
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