P-Glycoprotein (ABCB1) Inhibits the Influx and Increases the Efflux of ¹¹C-Metoclopramide Across the Blood–Brain Barrier: A PET Study on Nonhuman Primates

Abstract

PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of C-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. The regional brain kinetics of a tracer dose of C-metoclopramide (298 ± 44 MBq) were assessed in baboons using PET without ( = 4) or with ( = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution ( ), as well as the influx ( ) and efflux ( ) rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV⋅min) and the elimination slope ( ; min) from 30 to 60 min. Tariquidar significantly increased the brain distribution ofC-metoclopramide ( = 4.3 ± 0.5 mL/cm and 8.7 ± 0.5 mL/cm for baseline and ABCB1 inhibition conditions, respectively, < 0.001), with a 1.28-fold increase in ( < 0.05) and a 1.64-fold decrease in ( < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). correlated significantly ( < 0.0001) with AUC from 30 to 60 min ( = 0.95), with AUC from 0 to 30 min ( = 0.87), and with ( = 0.62). C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.

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

“…In humans, pharmacologic ABCB1 inhibition using cyclosporine A (CsA) or tariquidar resulted in pronounced increases in the plasma-to-brain permeation of the avid ABCB1 substrates 11 C-verapamil, (R)- 11 C-verapamil (15,16), and 11 C-Ndesmethyl-loperamide (17). 11 C-metoclopramide is a recently developed weak ABCB1 substrate PET tracer (18,19). PET data obtained with 11 C-metoclopramide in nonhuman primates suggested a dual role of ABCB1 in limiting the brain entry (influx hindrance) and controlling the clearance of 11 C-metoclopramide from the brain into the blood (efflux enhancement) (18,19).…”

Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib

“…This suggests that nanocarriers combined with ultrasound may be useful to bypass both the physical and the functional BBB, thus enabling the delivery of avid ABC-transporter substrates such as erlotinib to the brain, while overcoming efflux transporter-mediated multidrug resistance at the cancer-cell level [81]. However, ABC-transporter mediated efflux clearance from the brain parenchyma to the plasma compartment has been reported in different animal species [35,82,83]. It will be important to assess the impact of active efflux at the BBB and the blood-tumor barrier on tissue kinetics and therapeutic efficacy of ABC-transporter substrates delivered through the combination of ultrasound and complex drug delivery systems.…”

Impact of Acute Alcohol Exposure on P‐Glycoprotein Function at the Blood‐Brain Barrier Assessed Using 11C‐Metoclopramide PET Imaging

“…3 We validated 11 C-metoclopramide, a representative CNS-acting P-gp substrate, as a PET probe to study P-gp function at the BBB. 4 In four baboons, the P-gp inhibitor tariquidar drastically increased 11 C-metoclopramide distribution from arterial plasma to the brain across the BBB. 4 The 11 C-metoclopramide PET imaging was then performed using the same panel of animals to study the impact of acute alcohol exposure on P-gp function at the BBB (Figure 1a).…”

“…4 In four baboons, the P-gp inhibitor tariquidar drastically increased 11 C-metoclopramide distribution from arterial plasma to the brain across the BBB. 4 The 11 C-metoclopramide PET imaging was then performed using the same panel of animals to study the impact of acute alcohol exposure on P-gp function at the BBB (Figure 1a). Therefore, animals received an ethanol infusion to maintain controlled plasma concentrations of ethanol during PET acquisition (0.5-1.0 g/L).…”

“…: nonsignificant. Quantitative data obtained at baseline and after P-gp inhibition are reported from Auvity et al 4 PERSPECTIVES substrates is a valuable technique to study the impact of membrane transporter function on drug distribution to target and vulnerable tissues. This method complements PK studies and provides a relevant insight into transporter-mediated drugdrug interaction at the blood-tissue level.…”