OC-144093

The development of novel efflux pump inhibitors is an emerging and challenging research field. Besides the use of such excipients in cancer therapy, efflux pump inhibitors are gaining increasing interest with regards to drug delivery. In particular, inhibition of efflux pumps located in the intestine and the blood-brain barrier offers promising prospects. Nowadays, third-generation inhibitors, such as elacridar, zosuquidar, laniquidar, OC144-093 and tariquidar, have been evaluated in clinical trials. Apart from these small, molecular inhibitors, which will be discussed within the current review, a focus has been set on polymeric or polymer-based inhibitors, including poly(ethylene glycol) and derivatives, poloxamers and thiomers.

P-glycoprotein (P-gp) is a transmembrane drug efflux pump encoded by the MDR-1 gene in humans. Most likely P-gp protects organs against endogenous and exogenous toxins by extruding toxic compounds such as chemotherapeutics and other drugs. Many drugs are substrates for P-gp. Since P-gp is also expressed in the blood-brain barrier, P-gp substrates reach lower concentrations in the brain than in P-gp-negative tissues. Failure of response to chemotherapy of malignancies can be due to intrinsic or acquired drug resistance. Many tumors are multidrug resistant (MDR); resistant to several structurally unrelated chemotherapeutic agents. Several mechanisms are involved in MDR of which P-gp is studied most extensively. P-gp extrudes drugs out of tumor cells resulting in decreased intracellular drug concentrations, leading to the MDR phenotype. Furthermore, the MDR-1 gene exhibits several single nucleotide polymorphisms, some of which result in different transport capabilities. P-gp functionality and the effect of P-gp modulation on the pharmacokinetics of novel and established drugs can be studied in vivo by positron emission tomography (PET) using carbon-11 and fluorine-18-labeled P-gp substrates and modulators. PET may demonstrate the consequences of genetic differences on tissue pharmacokinetics. Inhibitors such as calcium-channel blockers (verapamil), cyclosporin A, ONT-093, and XR9576 can modulate the P-gp functionality. With PET the effect of P-gp modulation on the bioavailability of drugs can be investigated in humans in vivo. PET also allows the measurement of the efficacy of newly developed P-gp modulators.