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Oct 04, 2012
 |  BC Innovations  |  Cover Story

Slipping past P glycoprotein

NIH researchers have shown that sphingosine 1-phosphate receptor agonists such as Novartis AG's Gilenya fingolimod could transiently reduce P glycoprotein-mediated drug efflux and enhance drug delivery to the brain.1 The group at NIH's National Institute of Environmental Health Sciences thinks the transient mode of action of these agonists could avoid the adverse effects seen with direct P glycoprotein inhibitors.

The researchers now are elucidating the underlying mechanism and evaluating the approach for improving drug delivery to brain tumors.

P glycoprotein (MDR1; ABCB1; P-gp; CD243) is an active efflux transporter protein expressed by endothelial cells that line the blood brain barrier (BBB). The transporter exerts its neuroprotective effect by pumping out a range of potentially harmful molecules that enter the CNS from the blood. However, the transporter also complicates drug delivery to the CNS because it expels many therapeutics such as paclitaxel.

In cases in which a drug is a known substrate of P-gp, a straightforward strategy to enhance brain delivery is directly inhibiting P-gp. The problem with this approach is that direct P-gp inhibitors have caused unacceptable systemic toxicity in clinical trials, and nearly all such compounds have been discontinued.

Hanmi Pharmaceutical Co. Ltd. and partner Kinex Pharmaceuticals LLC are the only companies left with a disclosed oral P-gp inhibitor, HM30181A, but they are steering clear of the brain. The gastrointestinal-selective P-gp inhibitor is in Phase II trials to treat gastric cancer in combination with an oral formulation of paclitaxel and is in Phase I testing to treat advanced solid malignancies in combination with oral irinotecan.

According to David Miller, head of...

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