Abstract
473
Objectives At the blood-brain barrier (BBB) the ABC transporters Pgp and BCRP restrict brain distribution of many drugs. We assessed the effect of inhibiting Pgp on brain distribution of the dual Pgp/BCRP substrates [11C]tariquidar ([11C]TQD) and [11C]elacridar ([11C]ELA) and the selective Pgp substrate (R)-[11C]-verapamil ([11C]VPM)
Methods We conducted two consecutive 60 min [11C]-TQD, [11C]-ELA or [11C]-VPM PET scans with arterial blood sampling in healthy volunteers (n=5 for each radiotracer). At 1 h before start of the second PET scan an iv infusion of the Pgp inhibitor tariquidar (3.75 mg/min) was started and maintained throughout the scan. Regions of interest were defined MRI-based for whole brain grey matter and pituitary gland (PG; a region outside the BBB) and transferred to PET images. Uptake of each radiotracer was expressed as ratio of area under the time-activity curve (AUC) in brain or PG to AUC in plasma (AUCbrain or PG/AUCplasma)
Results In baseline scans without tariquidar, AUCbrain/AUCplasma was 15-, 10- and 5-times lower than AUCPG/AUCplasma for [11C]TQD, [11C]ELA and [11C]VPM, respectively. Pgp inhibition resulted in substantially lower increases in AUCbrain/AUCplasma relative to baseline scans for [11C]TQD (+14%) and [11C]ELA (+46%) as compared with [11C]VPM (+279%). For all radiotracers AUCPG/AUCplasma was not significantly different between scan 1 and scan 2. For [11C]VPM but not for [11C]TQD and [11C]ELA AUCbrain/AUCplasma and AUCPG/AUCplasma was comparable in scan 2
Conclusions After Pgp inhibition BCRP effectively compensates Pgp function at the BBB and restricts brain distribution of dual Pgp/BCRP substrates suggesting that brain distribution of dual substrates may only be substantially increased when both Pgp and BCRP are inhibited. PET with radiolabelled drugs may allow for estimating the maximum possible effects of transporter-mediated drug-drug interactions at the BBB without the need to inhibit the transporters when using the PG, which is not protected by the BBB, as a reference region