Drugs screened for effects on key transporters, risk of dangerous interactions

To reduce the risk of toxic drug interactions, UCSF's Kathy Giacomini, PhD, and colleagues are screening thousands of prescription drugs, testing how much they inhibit key proteins in kidney and liver cells that help clear medications from the body.

This is the first large-scale screening of drugs for their potential to inhibit drug transporters—proteins in cell membranes that control the entry and exit of drugs.

A recent Giacomini study found a half-dozen drugs that substantially inhibit one kidney cell transporter protein in particular at clinically relevant (or therapeutic) blood concentrations, thus raising the risk for drug interactions. But this finding also suggests new ways to protect the kidneys from drug-induced damage.

About this Article

UCSF researchers: Kathy Giacomini, PhD, is co-chair of the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine. The study was co-authored with recent UCSF postdoctoral scholars Yasuto Kido, PhD, and Par Matsson, PhD; and carried out in collaboration with the School of Pharmacy’s Small Molecule Discovery Center.

Journal: Kido Y, Matsson P, and Giacomini KM, “Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2,” Journal of Medicinal Chemistry, Vol. 54. Issue 13. p. 4548-4558 (2011).

Funding: National Institutes of Health (NIH)

The challenge

Each year more than two million people in U.S. suffer severe adverse drug reactions that can result in death and disability. About one-quarter of those reactions are caused by the interactive effects of taking multiple drugs at the same time.

It is well known that some of those problems occur when one drug inhibits enzymes that would normally break down, or metabolize, a second drug. Thus the second drug accumulates in the body to toxic levels. (Drugs are tested for such effects before approval and their prescribing information may include warnings.)

But increasingly studies are finding that such drug-drug interactions (DDIs) also occur when drugs inhibit specific proteins in cell membranes, called transporters, which control the passage of drug molecules in and out of cells.

In the kidneys, the inhibition of transporter proteins by one drug may reduce or prevent a second drug’s clearance from the body. Since most prescription drugs exit through the kidneys and then in urine, this can cause toxic levels in the body or even in the kidney itself.

The research

In a recently published study, Kathy Giacomini, PhD, and colleagues analyzed the effects of 910 prescription drugs on the function of one specific transporter in the membranes of in vitro kidney cells.

They found 52 drugs reduced transporter function by 50 percent or more at clinically relevant concentrations—in other words, the amount per liter of blood after typical doses.

Most significantly, six of those drugs had the unbound blood concentrations required to inhibit organic cation transporter 2 (OCT2). The other drugs were bound to blood plasma proteins at higher rates. The researchers believe that only unbound drugs can inhibit the transporters.

OCT2 controls the first step toward the kidneys clearing most drugs from the body. It is specifically responsible for the kidney clearance of metformin, which is the most commonly prescribed drug for type 2 diabetes, as well as for several drugs used for treating cancer and HIV infection.

The scientists looked for structural similarities between the drug molecules that inhibit OCT2 as a potential new safety screen for drugs under development. They saw notable categories of similarity, but also found that they varied greatly. This suggests the drugs may inhibit the transporters in different ways.

The implications

Giacomini et al found six drugs which, at clinically relevant concentrations, so specifically and significantly inhibited the OCT2 protein’s function and thus, potentially, kidney drug clearance that:

  • They merit follow-up clinical studies to determine their potential for generating drug-drug interactions.
  • They could be used to test the effect of inhibiting OCT2 on the clearance or toxic accumulation of other drugs.
  • They might be used to protect the kidneys from nephrotoxic (i.e. kidney-damaging) cancer and anti-retroviral drugs by inhibiting those drugs’ entry into cells.

Indeed, this was a preliminary study for the largest transporter-related DDI project to date. In a National Institutes of Health (NIH) funded partnership with Optivia Biotechnology of Menlo Park announced in April 2011, the Giacomini lab is studying the effects of 2,000 drugs on key liver and kidney transporters to identify the most significant ones.


School of Pharmacy, Department of Bioengineering and Therapeutic Sciences, PharmD Degree Program

About the School: The UCSF School of Pharmacy aims to solve the most pressing health care problems and strives to ensure that each patient receives the safest, most effective treatments. Our discoveries seed the development of novel therapies, and our researchers consistently lead the nation in NIH funding. The School’s doctor of pharmacy (PharmD) degree program, with its unique emphasis on scientific thinking, prepares students to be critical thinkers and leaders in their field.