Leslie Benet wins Ebert Prize
During his illustrious half-century career, UCSF School of Pharmacy faculty member Leslie Benet, PhD, has authored more than 400 peer-reviewed publications, many helping to define the field of pharmacokinetics—how the body absorbs, distributes, metabolizes, and excretes medications—or as he once put it, “what the body does to the drug.”
Now a Benet paper examining how the uptake of certain types of drugs by cells in the liver is affected by toxins resulting from chronic kidney disease (CKD) has won the Ebert Prize, the oldest U.S. pharmacy award.
Established in 1873, the prize recognizes the author of the best original investigation of a medicinal substance appearing in the Journal of Pharmaceutical Sciences over the prior year.
Published in September, 2011, the paper entitled “Effects of Uremic Toxins on Transport and Metabolism of Different Biopharmaceutics Drug Disposition Classification System Xenobiotics” includes findings with key implications for the treatment of CKD patients and for drug development.
The prize is administered by the American Pharmacists Association Academy of Pharmaceutical Research and Science (APhA-APRS). Benet will be formally honored at the APhA annual meeting in Los Angeles in March.
The paper was co-authored by Maribel Reyes, PhD, now a clinical pharmacologist at Actelion Pharmaceuticals. She earned her doctorate in Benet’s lab in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.
How declining kidneys affect drug uptake by liver cells
It is well understood that the declining renal function of CKD alters the pharmacokinetics of drugs that are excreted unchanged in urine, usually requiring dose adjustments. Also, studies have shown uremic toxins resulting from reduced waste excretion inhibit some drug-metabolizing enzymes.
But Benet’s prize-winning paper took a different approach, investigating whether uremic toxins affected the entry and exit (uptake and efflux) of certain classes of drugs into liver hepatocyte cells containing those enzymes.
In recent years, pharmacokinetics research has begun focusing on the role of drug transporters—cell membrane proteins that control the passage of drug molecules, and thus their metabolism and disposition. Prior studies in Benet’s lab had shown that hepatocyte transporters were vital to the uptake and efflux of certain drugs and their exposure to metabolizing enzymes.
To examine the effect of uremic toxins on those hepatic transporters, Benet and Reyes looked at drugs classified by factors affecting their likely reliance on the transporters to gain entry to and exit from the liver cells.
The scientists hypothesized that highly soluble drugs that readily permeate cell membranes and are extensively metabolized (Class 1 under the four-class Biopharmaceutics Drug Disposition Classification System or BDDCS) would be unlikely to be affected by toxin-inhibited transporters. On the other hand, low solubility drugs that don’t permeate and are poorly metabolized (Class 4), would depend on transporter uptake (and transporter-enzyme interplay) and thus would be greatly affected.
Benet and Reyes tested this by measuring the uptake of a drug in Class 1, 2, and 4, as well as a model substrate—a molecule optimally taken up by the transporters—by rat hepatocyte cells and human cells expressing hepatocyte drug transporters under various conditions, including in the presence of:
- normal human blood serum
- individual uremic toxins
- blood serum from patients undergoing hemodialysis (which contains a mix of toxins with potentially synergistic effects)
The researchers found that, indeed, some uremic toxins partially inhibited uptake of the model substrate as well as the drugs expected to be dependent on transporters, but had no effect on a Class 1 drug. Also, uptake of the Class 2 drug and possibly efflux of the Class 4 drug (both treatments for high blood pressure) were inhibited by blood serum from hemodialysis patients.
The paper notes that inhibition of membrane transporters rather than intracellular enzymes is what changes metabolism of the drugs and concludes: “In CKD patients ... dose adjustment for nonrenally excreted drugs may be necessary for prevention of drug toxicity or to reach the desired therapeutic effect.”
And Benet and Reyes add: “Being able to predict (based on BDDCS class) if a drug will be affected by uremic toxins can be useful in deciding what studies may be necessary during drug development.”