Process of Elimination
Understanding the genetic differences that affect how the body excretes drugs may improve therapies for cystic fibrosis patients.
With this understanding, new and existing drugs can be evaluated to minimize side effects and maximize therapeutic effectiveness in patients.
Paul Beringer, Pharm.D., associate professor of clinical pharmacy at the USC School of Pharmacy, is contributing to this research by studying how a protein transporter called P-glycoprotein (P-gp) affects how specific drugs are eliminated from the body.
Located in the gastrointestinal tract, kidneys, liver and central nervous system, P-gp acts as a membrane pump that moves drugs from inside to outside the cell.
“Every person has this pump to keep the inside of the cell free from foreign substances,” Beringer says.
After a drug is absorbed into the bloodstream, it is eliminated through the liver or the kidneys. Kidney filtration—or renal clearance—allows the body to excrete toxins through the urine.
“Due to genetic differences, some individuals are born with more efficient P-gp, which is associated with faster renal clearance,” he says. “A patient with enhanced renal clearance eliminates drugs into the urine at an increased rate. If an individual makes more P-gp, then they will require more of specific drugs to receive a therapeutic effect.”
These genetic differences, of which there are about 1.4 million variations, are referred to as polymorphisms.
Over the last decade, scientists have linked the gene MDR1 to the production of P-gp, says Beringer. “Within MDR1, there are some polymorphisms that can cause over-production of P-gp, while others can cause under-production,” he says.
Collaborative research is currently underway at the USC School of Pharmacy and Keck School of Medicine to evaluate the relationship between MDR1 genotypes and the renal clearance of drugs that involve P-gp.
Beringer is focusing on improving therapies for patients with cystic fibrosis (CF), a life-threatening genetic disease that affects one in 30,000 children and adults living in the United States.
“CF is caused by a defect of the CFTR gene that causes the faulty transport of sodium and chloride [salt],” Beringer says. “These patients develop an abundance of thick mucus secretions in the lungs, pancreas and sweat glands, which results in chronic pneumonia.”
Beringer, along with Bertrand Shapiro, M.D., professor of clinical medicine at the Keck School, and other pharmacy faculty members, will study how 24 adults—12 with CF and 12 healthy—eliminate drugs in relation to their P-gp production.
The clinical trial will consist of three outpatient visits, where patients will be given a combination of drugs that are transported by P-gp, as well as drugs that stop the transporter from working. Renal clearance will be measured in both patient populations.
Past research has shown that CF patients exhibit enhanced renal clearance with certain antibiotics, but no explanation for this difference had been confirmed, Beringer says.
“P-gp enhances chloride transport, which may be why CF patients produce more to compensate for their genetic defect,” Beringer says. “It is also possible for CF patients to have an MDR1 polymorphism that increases P-gp production.”
“If proven, this would allow clinicians to appropriately dose antibiotics that involve P-gp, allowing for greater efficacy,” Shapiro says. “By pinpointing the mechanism involved, it is also possible to develop more effective antibiotics.
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