The impact of the BBB on the pharmacokinetics of drugs: Investigations by PET

The blood brain barrier (BBB) impedes many neuropharmaceuticals from eliciting their desirable pharmacological or toxicological effect. A crucial component of this barrier is the ATP-driven drug efflux pump P-glycoprotein, which prevents the entry of xenobiotics into the brain. P-gp’s activity is also implicated in pathologies such as neurodegenerative disorders and refractory brain diseases. PET allows non-invasive in vivo assessment of P-gp’s impact on drug disposition in the CNS. Recently, a number of P-gp ligands have been synthesized for PET studies. Using the most-established P-gp ligand [11C]-verapamil, as an example, methods to quantify P-gp activity at the BBB are discussed and compared. Drug-drug interaction (DDI) studies in the CNS following modulation of P-gp activity are also presented. Finally, the application of PET methodology to study P-gp function in the diseased brain is discussed.