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. Although 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 concerns with the commonly used pain reliever diclofenac may be linked to a poorly understood drug-metabolizing enzyme, according to recent research. The expression of this enzyme can vary as much as 3000 times between individuals.
conclusions of the study published in Clinical Pharmacology and Therapeutics, can be used to develop methods to identify individuals who are vulnerable to severe side effects of diclofenac. These methods could also help establish safe dosing guidelines for specific demographic groups, including women, young children, and individuals of certain ethnic backgrounds.
Diclofenac, used to fight pain and inflammation associated with arthritis, was available in the US as an over-the-counter drug until 2013, when the Food and Drug Administration restricted its use to prescription only after reports of the drug causing heart damage. More than 10 million prescriptions are written annually in the United States. It is also one of the most widely used non-steroidal anti-inflammatory drugs in the world. This includes many countries in Asia, Africa and the Middle East where over-the-counter diclofenac is still allowed.
“The majority of patients taking diclofenac have arthritis, and many of them are at risk for heart disease,” said senior author Bhagwat Prasad, an associate professor in the College of Pharmacy and Pharmaceutical Sciences at Washington State University. “Therefore, there is concern that using diclofenac may increase the risk of cardiovascular events such as heart attack and stroke.”
Previous findings by the WSU team revealed high expression of UGT2B17, an enzyme known to be involved in the metabolism of diclofenac. This study showed that levels of the enzyme are much lower in women than in men, which the researchers believe could explain the increased risk of heart damage in women taking diclofenac. They also found that the enzyme is largely absent in children under the age of nine, and found large ethnic differences in the number of people missing the gene for the enzyme altogether, ranging from about 20% of Caucasians to about 90%. Japanese people.
In this new study, WSU researchers used human liver and intestinal samples along with computer modeling to quantify the degree to which this enzyme contributes to the metabolism of diclofenac compared to other related enzymes. They found it to be a major player, supporting the idea that low levels of the UGT2B17 enzyme may cause the heart damage associated with diclofenac use.
“No one knew why this cardiac toxicity was happening in some people,” said first author Deepak Ahire, a graduate student in WSU’s College of Pharmacy and Pharmaceutical Sciences. “Our study shows for the first time that UGT2B17 is important in the metabolism of diclofenac and suggests that differences in UGT2B17 expression make people’s responses to diclofenac so variable, leading to toxicity in some cases while the drug simply doesn’t work in others.”
Ahire said their study found that this enzyme metabolizes diclofenac primarily in the gut, unlike other related enzymes that function primarily in the liver. As a result, the effect the researchers see is typical of oral diclofenac tablets, which provide the fastest absorption and pain relief. Prasad said that just under half of all prescriptions in the U.S. are for oral diclofenac.
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 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 the local market.
The WSU researchers are currently validating their findings in a pilot clinical trial. Their next step would be to continue working with large hospitals to study the link between diclofenac and heart damage in patients’ electronic medical records.
Reference: “Intestinal Metabolism of Diclofenac by UGT2B17 Polymorph Correlates with Its Highly Variable Pharmacokinetics and Safety in Different Populations” by Deepak Ahire, Scott Hayward, and Bhagwat Prasad, April 12, 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, part of the National Institutes of Health.
#Researchers #point #source #side #effects #commonly #painkillers
