Researchers point to the source of serious side effects in widely used painkillers

Prescription medicine concept

Prescription medicine concept

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that is 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.

Recent research suggests that the safety issues associated with the commonly used pain reliever diclofenac may be linked to a poorly understood drug metabolizing enzyme. The expression of this enzyme can vary up to 3,000 times from individual to individual.

The results of a study published in Clinical Pharmacology & Therapeutics, have the potential to be used for the development of methods to identify individuals susceptible to severe side effects of diclofenac. These methods could also be helpful in establishing safe dosing guidelines for specific demographic groups, including women, young children, and those from certain ethnic backgrounds.

Diclofenac was used to combat pain and inflammation associated with arthritis and was available over-the-counter in the United States until 2013, when the Food and Drug Administration restricted it to prescription use after reports of the drug causing heart damage. More than 10 million prescriptions are issued annually in the United States. It is also one of the most commonly used non-steroidal anti-inflammatory drugs worldwide. This includes many countries in Asia, Africa and the Middle East that still allow the use of diclofenac over the counter.

“Most patients using diclofenac have arthritis, and many of them are at risk for heart disease,” said senior author Bhagwat Prasad, associate professor at Washington State University College of Pharmacy and Pharmaceutical Sciences. “There is therefore a concern that taking diclofenac could put them at even greater risk of cardiovascular events such as heart attack and stroke.”

Previous results from the WSU team had identified a high level of variability in the expression of UGT2B17, an enzyme that has a known role in diclofenac metabolism. This study showed that the enzyme is present in much lower amounts in women than in men, which the researchers believe could 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 discovered large ethnic disparities in the number of people lacking the gene for the enzyme altogether, ranging from about 20% of Caucasians to about 90%. the japanese.

In this new study, the WSU researchers used human liver and intestine samples along with computational models 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 could be the cause of heart damage associated with diclofenac use.

“No one knew why this cardiac toxicity occurs in some individuals,” said first author Deepak Ahire, a graduate student at the WSU College of Pharmacy and Pharmaceutical Sciences. “Our study demonstrated 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 diverse, leading to toxicity in some while on the drug.” it just doesn’t work for others.”

Ahire said her study found that this enzyme metabolizes diclofenac primarily in the gut, unlike other related enzymes that are primarily active in the liver. As a result, the effect the researchers are seeing is specific to orally taken diclofenac tablets, which offer the fastest absorption and pain relief. Just under half of the prescriptions written for the drug in the US are for oral diclofenac, Prasad said.

The researchers’ findings suggest that it may be possible to use genetic testing to help healthcare providers assess safety risks before prescribing diclofenac. Prasad also noted that drug regulatory agencies in countries where diclofenac is still available over the counter should consider conducting potency testing to determine the optimal dose of the drug for their local market.

The WSU researchers are currently in the process of confirming their results in a pilot clinical study. Her next step would be to work with major hospitals to study the link between diclofenac and heart damage in electronic medical records.

Reference: “The gut metabolism of diclofenac by polymorphic UGT2B17 correlates with its highly variable pharmacokinetics and safety across populations” by Deepak Ahire, Scott Heyward and Bhagwat Prasad, April 12, 2023, Clinical Pharmacology & Therapeutics.
DOI: 10.1002/cpt.2907

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, part of the National Institutes of Health.

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