Why the bad taste?

A novel mechanism that explains the bitter pill

Bad taste

Numerous medications can affect a patient’s sense of taste and smell adversely. These effects even can persist long after drug cessation. Drug-induced taste disorders can impact significantly patients’ quality of life, dietary choices and emotional states. More importantly, they can provoke noncompliance problems, especially in children and elderly patients.

In a recent issue of the Journal of Biological Chemistry, a research team at the University of Washington described a novel mechanism for active drug accumulation and secretion in salivary gland epithelial cells that leads to the lingering bad taste of metformin, a frontline prescription drug used in the treatment of type 2 diabetes. Joanne Wang, a professor at the School of Pharmacy, led the team.

“Dr. Wang’s lab has identified a transporter protein in the salivary glands that takes up drug compounds from the circulating blood and transfers them to the saliva they produce, giving us new insight into how certain medications change how foods taste,” said Richard Okita of the National Institutes of Health’s National Institute of General Medical Sciences, which partially funded the research. “This discovery could potentially be used in drug development to prevent excessive accumulation of a drug in saliva glands and reduce related conditions such as drug-induced dry mouth.”

While several factors might contribute to drug-induced taste disturbance, continuous secretion of drug molecules into the saliva appears to be one of them.

Very little is known regarding how the salivary gland secretory cells secrete drugs or other xenobiotics into the saliva. Most drugs have been assumed to enter saliva by passive diffusion, a process characterized by downhill, nonmediated diffusion of drug molecules across the membranes of salivary gland epithelial cells. However, passive diffusion cannot explain salivary secretion of hydrophilic drugs or account for prolonged drug presence in saliva long after systemic drug elimination.

Wang’s team found that salivary glands selectively and highly express a polyspecific drug transporter called organic cation transporter 3, or OCT 3 for short. Present on both basolateral (blood-facing) and apical (saliva-facing) membranes of the salivary gland acinar cells, OCT3 is responsible for the concentration of metformin in secretory epithelial cells and its subsequent slow release into saliva.

The researchers showed that metformin was transported actively into salivary glands of wild-type mice at levels as high as those seen in the kidney and liver. Deletion of the gene for OCT3 in mice abolished active drug uptake and accumulation in salivary glands.

This is the first time that a carrier-mediated mechanism has been demonstrated for drug accumulation and secretion in salivary glands, Wang said.

The primary function of salivary glands is to secrete saliva, which plays an important role in oral health, nutrient digestion and immunity to microbial infection. Healthy adult salivary glands secrete about three-quarters of a liter to 1.5 liters of salivary fluid each day, and dysfunction of the salivary glands can lead to xerostomia, more commonly known as dry mouth.

While xerostomia may have many origins, Wang said, excessive accumulation of a drug within the salivary glands may lead to tissue toxicity and gland dysfunction. She added that, in this study, OCT3-mediated active uptake led to very high levels of drug accumulation in salivary glands, which may intensify drug toxicity to the secretory epithelial cells.

“Designing drugs that are not OCT3 substrates might prevent drug-induced taste disorders and salivary gland toxicity mediated by OCT3,” Wang said.

Sarah C.B. Guthrie is director of communications at the University of Washington School of Pharmacy.