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PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate 11 C-metoclopramide in humans to elucidate the impact of ABCB1 function on its brain kinetics. Methods: Ten healthy male subjects underwent 2 consecutive 11 C-metoclopramide PET scans without and with ABCB1 inhibition using cyclosporine A (CsA). Pharmacokinetic modeling was performed to estimate the total volume of distribution ( V  T ) and the influx ( K  1 ) and efflux ( k  2 ) rate constants between plasma and selected brain regions. Furthermore, 11 C-metoclopramide washout from the brain was estimated by determining the elimination slope ( k  E,brain ) of the brain time-activity curves. Results: In baseline scans, 11 C-metoclopramide showed appreciable brain distribution ( V  T = 2.11 ± 0.33 mL/cm 3 ). During CsA infusion, whole-brain gray matter V  T and K  1 were increased by 29% ± 17% and 9% ± 12%, respectively. K  2 was decreased by 15% ± 5%, consistent with a decrease in k  E,brain (-32% ± 18%). The impact of CsA on outcome parameters was significant and similar across brain regions except for the pituitary gland, which is not protected by the BBB. Conclusion: Our results show for the first time that ABCB1 does not solely account for the "barrier" property of the BBB but also acts as a detoxifying system to limit the overall brain exposure to its substrates at the human blood-brain interface.

Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate 11C-Metoclopramide Assessed with PET Imaging in Humans

Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate ¹¹C-Metoclopramide Assessed with PET Imaging in Humans