Supplement: Testing Transporters

Testing Transporters By Jack Lucentini ARTICLE EXTRAS Innovative Technology Technology Roundup Greater Philadelphia Innovation --> Bristol Myers-Squibb Rutgers-Camden Institute Neuronetics Temple University University of Pennsylvania Tengion Kimmel Cancer Center Orphagenix BioNanomatrix FDA expectations for preclinical drug testing as part of new drug applications are growing. That promises good business for Exton, Pa.-b

Jan 1, 2008
Jack Lucentini
Testing Transporters
By Jack Lucentini

FDA expectations for preclinical drug testing as part of new drug applications are growing. That promises good business for Exton, Pa.-based Absorption Systems, company officials say. The firm develops and performs assays to predict the absorption, distribution, metabolism, and excretion profiles of small molecules in humans.

"I don't have numbers on how it will impact the business, but it will be dramatic," says company president, CEO, and cofounder Patrick Dentinger. He was referring specifically to emerging Food and Drug Administration recommendations that drug developers study how drugs affect each other's activities through their interactions with the body's transport proteins.

The company is well positioned to compete in a new market for assays, thanks to these recommendations, Dentinger says. The guidelines prompted "an uptick in clients who came to us" for advice on implementing them, he adds. The company's clients include Ono Pharmaceuticals of Japan, and Genzyme and Elixir Pharmaceuticals, both in Cambridge, Mass.

"We have what we think is the only human cell line that expresses only P-gp as an efflux pump." --Chris Bode

Drugs can interact in the body at the enzyme or the transporter level, says Ismael Hidalgo, company cofounder and chief scientist. Enzyme-level interaction, well known for years, occurs when an enzyme chemically alters a drug. If a second drug inhibits the enzyme, that inhibition indirectly affects the first drug's activity. In transporter-level interaction, two or more drugs interact with the same protein transporter (which helps molecules cross a membrane); this "can lead to toxicity, side effects, or could make the drug ineffective," Hidalgo says, but it leaves the drug unchanged chemically, making the interaction harder to assess.

Absorption Systems' assay format for this, developed with close attention to FDA advice, consists of a membrane of specially grown, tightly linked human epithelial cells dividing two compartments, Hidalgo says. A drug on one side of the membrane might flow through it, depending on its transporter interactions. Several factors can complicate this seemingly simple test. For one thing, many transporter types exist; sorting out the one that causes a given effect is tricky.

Thus, Absorption Systems is engineering cells to express only one transporter. It has created the first such cell line, with the so-called P-glycoprotein (P-gp) efflux transporter, says Chris Bode, the company's vice president for corporate development. That's the most relevant transporter at the moment, he adds, as the draft guidance suggests focusing only on P-gp for now. P-gp might have many drug interactions, because it's found at pharmacologically important barriers, including the small intestine, liver, kidney, and blood-brain barrier, Bode and colleagues say.

"We have what we think is the only human cell line that expresses only P-gp" as an efflux pump, Bode says. That should help the company fare well when it starts commercializing the assay in the first quarter of 2008, says Dentinger. Two other reasons he's optimistic: Absorption Systems is one of just a handful of companies worldwide known to offer a full suite of assays in its field, and the FDA mandates are speeding acceptance of the technology.