Co-administration of P-glycoprotein inhibitors with bortezomib improves therapeutic access to the CNS

The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. Here, the authors sought to determine if they could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. They used overexpressed cell lines, genetic mouse models, and systemic administration of an inhibitor to demonstrate that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. SMN levels were also increased in the CNS of SMA mice treated with both drugs. Tariquidar and bortezomib treated mice also lived longer and had improved motor function compared with tariquidar-alone, bortezomib-alone, and vehicle treated counterparts. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.

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Foran E, Kwon DY, Nofziger JH, et al.CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy. Neurobiol Dis. 2016 Jan 11;88:118-124.