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

Abstract

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 5 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.

Imaging P‐Glycoprotein Function at the Blood–Brain Barrier as a Determinant of the Variability in Response to Central Nervous System Drugs

“…We have characterized the interaction between [ 11 C]metoclopramide and the clinically validated P‐gp inhibitor cyclosporine A in healthy human volunteers with PET imaging . Our results strongly suggested that [ 11 C]metoclopramide is transported by P‐gp at the human BBB as reflected by a 29% increase in its total volume of distribution ( V T ) in the brain following cyclosporine A administration.…”

“…Brain uptake of [ 11 C]metoclopramide was substantially higher than that of previously characterized avid P‐gp substrates for PET, supporting that metoclopramide is a weak P‐gp substrate that can enter the brain despite being transported by P‐gp. Kinetic analysis revealed that the cyclosporine A–induced increase in brain V T (= K 1 / k 2 ) was mainly caused by a decrease in the efflux rate constant of [ 11 C]metoclopramide from brain into plasma ( k 2 ) rather than by an increase in the influx rate constant from plasma into brain ( K 1 ) ( Figure ) . This implies that P‐gp exerts a different impact on the neuropharmacokinetics of the weak P‐gp substrate metoclopramide as compared with previously used avid P‐gp substrates for PET, for which P‐gp inhibition only increased K 1 ( Figure ) .…”

“…This implies that P‐gp exerts a different impact on the neuropharmacokinetics of the weak P‐gp substrate metoclopramide as compared with previously used avid P‐gp substrates for PET, for which P‐gp inhibition only increased K 1 ( Figure ) . P‐gp does not solely contribute to the barrier property of the BBB in limiting influx of drugs from plasma into brain (influx hindrance) but also acts as a detoxifying system to promote clearance of its substrates from the brain (efflux enhancement) ( Figure ) . Whereas the influx hindrance process effectively keeps drug concentrations in the brain low, efflux enhancement predominantly decreases the half‐life of drugs in the brain .…”

“…The [ 11 C]metoclopramide PET images were originally published in ref. , Tournier, N. et al . Impact of P‐glycoprotein function on the brain kinetics of the weak substrate 11 C‐metoclopramide assessed with PET imaging in humans.…”

Challenges in Neuropharmacology

“…In this issue, Bauer and Langer commented on the discussion on the role of P‐gp at the blood–brain barrier by summarizing positron emission tomography studies using 11 C‐labeled P‐gp substrates, such as verapamil or metoclopramide. The latter compound is considered as a weak P‐gp substrate, but interaction studies with cyclosporine as inhibitor could demonstrate that the uptake into the brain was increased whereas the efflux was decreased, resulting in elevated metoclopramide exposure in the brain …”