Mefenamic acid, a common anti-inflammatory drug already approved for pain management, has been found to significantly reduce the formation of a toxic compound known as p-cresol sulfate in people with kidney disease with a minimal dose.
"Right now, there's nothing drug-wise that we can use to reduce this toxin quickly," says Tony Kiang, associate professor in the Faculty of Pharmacy & Pharmaceutical Sciences and lead author on the study.
The body makes a compound called p-cresol when it breaks down proteins and amino acids. These compounds travel to the liver, which converts them into p-cresol sulfate, a toxic uremic substance. "This is a natural process," Kiang says. The body's addition of the sulfate group makes it easier for the kidneys to eliminate the toxins with urine, he explains.
A healthy person's kidneys quickly get rid of the toxic sulfates. However, for the approximately 10 per cent of the population with chronic kidney disease, their kidneys aren't able to eliminate these toxins efficiently and they can accumulate to dangerous levels.
All the evidence suggests that p-cresol sulfate is the most toxic of the hundreds of uremic toxins in the body, Kiang says. "That's why we targeted this particular toxin."
"High levels of this toxin are correlated with heart disease, further progression of kidney disease, brain fog, central nervous system diseases, bone loss and even cancer," he says.
"Even dialysis is not a very efficient approach to eliminate this toxin," he adds. So the level of toxin gets higher.
Current approaches to managing this problem revolve around strict dietary changes. However, these changes work slowly and are not an ideal solution when fast action is needed.
Not only does mefenamic acid work very quickly, it's also selective in what it targets, affecting just the harmful compounds while leaving the non-toxic compounds intact, says Kiang.
"It essentially blocks the metabolic pathway in the liver that generates this toxin, so it's like a switch you can turn off."
Since very low doses of mefenamic acid are needed to achieve the intended effect, kidney disease patients have less likelihood of side-effects from the drug. The drug is naturally eliminated from the body, so it is unlikely to accumulate or create new problems for people with kidney disease who are exposed to very small doses of this medication.
Mefenamic acid is already available in a generic version with no associated patent, so it's a cost-effective therapy, explains Kiang. And since the drug has already been on the market for many years, its path from the lab to this new clinical use could be short. Kiang describes it as "a very effective tool" and he anticipates few or no drawbacks during its testing and eventual clinical use.
To identify potential sulfotransferase inhibitors that might work for this purpose, Kiang did a systematic screening of several available options and found mefenamic acid was the most potent and promising option, which was why he further explored the efficacy of the drug in this context.
To measure levels of p-cresol sulfate, Kiang used liquid chromatography mass spectrometry, a highly specialized technique that is able to detect the amount of toxins present based on their mass and charge. He plans to look at preclinical models next, testing the effect of the drug in different doses in animals before it can progress to clinical testing.
The research was supported by a Natural Sciences and Engineering Research Council of Canada Discovery Grant.
