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Popular Weight-Loss Drug May Be Toxic

Orlistat affects therapeutic potential of some anticancer drugs (Dec. 10)

A researcher at the University of Rhode Island has discovered that the popular weight-loss drug orlistat inhibits a key enzyme that may lead to “severe toxicity of internal organs, such as the liver and kidney.” The inhibition is irreversible and can be caused by a low level of the drug.

Professor Bing-fang Yan’s study, funded by the National Institutes of Health, also found that the drug alters the efficacy of medicines and limits the effectiveness of some anticancer drugs.

Part of the research was published online in Biochemical Pharmacology. Yan also alerted the FDA to his findings.

Orlistat, which was originally approved by the FDA in 1999 as the prescription drug Xenical (Genentech), was approved in 2007 as the over-the-counter medication Alli (GlaxoSmithKline). It has been the most commonly used medicine to treat obesity for more than a decade, Yan said.

“Since it has been available over-the-counter, there has been a drastic increase of toxicity among patients using the drug,” Yan remarked. “It has been linked to severe liver failure, acute pancreatic failure, and acute renal failure.”

Yan said that orlistat works in the intestinal tract by preventing fat from being absorbed by the body. It is generally accepted that the drug remains in the intestine and that the body does not absorb it.

“But orlistat is reportedly absorbed, and certain internal organs, such as the liver and kidney, are exposed to this drug upon absorption,” he said.

The new study showed that orlistat is a potent inhibitor of carboxylesterase-2, which is a major detoxification enzyme in the liver, kidney, and gastrointestinal tract. “When the activity of this enzyme drops in those organs, toxicity increases or the efficacy of some drugs is altered,” Yan said.

Carboxylesterase-2 is known to metabolize a wide range of medicines, including aspirin and the cancer prodrugs irinotecan and pentyl carbamate of p-aminobenzyl carbamate of doxazolidine (PPD).

“This study shows that orlistat profoundly alters the therapeutic potential of the anticancer drugs,” Yan said. “In the case of the anticancer drugs, it weakens their effectiveness.”

The prior or current presence of orlistat with one of the anticancer drugs resulted in cancer cells being far more prolific.

Yan was also interested in the effects of orlistat on aspirin’s activity as a blood thinner. “Orlistat would increase the therapeutic potential of aspirin, which may increase the tendency of bleeding,” he said.

Source: University of Rhode Island; December 10, 2012.

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