Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

Abstract

[11C]metoclopramide PET imaging provides a sensitive and translational tool to explore P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Patients with neurological diseases are often treated with cytochrome (CYP) modulators which may impact the plasma and brain kinetics of [11C]metoclopramide. The impact of the CYP inducer carbamazepine or the CYP inhibitor ritonavir on the brain and plasma kinetics of [11C]metoclopramide was investigated in rats. Data obtained in a control group were compared with groups that were either orally pretreated with carbamazepine (45 mg/kg twice a day for 7 days before PET) or ritonavir (20 mg/kg, 3 h before PET) (n = 4 per condition). Kinetic modelling was performed to estimate the brain penetration (VT) of [11C]metoclopramide. CYP induction or inhibition had negligible impact on the plasma kinetics and metabolism of [11C]metoclopramide. Moreover, carbamazepine neither impacted the brain kinetics nor VT of [11C]metoclopramide (p > 0.05). However, ritonavir significantly increased VT (p < 0.001), apparently behaving as an inhibitor of P-gp at the BBB. Our data suggest that treatment with potent CYP inducers such as carbamazepine does not bias the estimation of P-gp function at the BBB with [11C]metoclopramide PET. This supports further use of [11C]metoclopramide for studies in animals and patients treated with CYP inducers.

St. John's wort extract with a high hyperforin content does not induce P‐glycoprotein activity at the human blood–brain barrier

“…This is because [ 11 C]metoclopramide is primarily metabolized by CYP2D6, 26 which is not inducible via PXR 27 . This is consistent with preclinical data showing that the potent CYP inducer carbamazepine had no effect on the plasma pharmacokinetics and metabolism of [ 11 C]metoclopramide in rats 28 . Moreover, [ 11 C]metoclopramide lacks brain‐penetrant radiolabeled metabolites 29 and shows good passive permeability at the BBB resulting in appreciable brain distribution even when P‐gp is fully functional.…”

“…27 This is consistent with preclinical data showing that the potent CYP inducer carbamazepine had no effect on the plasma pharmacokinetics and metabolism of [ 11 C]metoclopramide in rats. 28 Moreover, [ 11 C]metoclopramide lacks brain-penetrant radiolabeled metabolites 29 and shows good passive permeability at the BBB resulting in appreciable brain distribution even when P-gp is fully functional. [ 11 C]Metoclopramide can be considered as a "weak" P-gp substrate, 16 which…”

Performance and Sensitivity of [99mTc]Tc-sestamibi Compared with Positron Emission Tomography Radiotracers to Measure P-glycoprotein Function in the Kidneys and Liver

“…If metabolism occurs, it should (i) at least not involve CYP3A enzymes and (ii) radiolabeled metabolites should show a minor contribution to the imaging signal in the investigated organ. [ 11 C]­metoclopramide is mainly metabolized by CYP2D6 , and chronic treatment of rats with the CYP3A4 and CYP2B6 inducer carbamazepine had no effect on in vivo [ 11 C]­metoclopramide metabolism . [ 11 C] N -desmethyl-loperamide has been designed as a metabolically stable PET probe in humans, whose metabolism in mice was only affected to a minor extent by the potent CYP3A4 inhibitor ketoconazole .…”

“…[ 11 C]metoclopramide is mainly metabolized by CYP2D6 28 , 29 and chronic treatment of rats with the CYP3A4 and CYP2B6 inducer carbamazepine had no effect on in vivo [ 11 C]metoclopramide metabolism. 30 [ 11 C] N -desmethyl-loperamide has been designed as a metabolically stable PET probe in humans, 31 whose metabolism in mice was only affected to a minor extent by the potent CYP3A4 inhibitor ketoconazole. 32 On the other hand, ( R )-[ 11 C]verapamil is extensively metabolized involving CYP3A enzymes.…”