Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [ 11 C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier.
Louise BreuilNora ZianiSarah LeterrierGaëlle HugonFabien CailléViviane BouilleretCharles TruilletMaud GoislardMyriam El BialiMartin BauerOliver LangerSébastien GoutalNicolas TournierPublished in: Pharmaceutics (2022)
[ 11 C]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 [ 11 C]metoclopramide. The impact of the CYP inducer carbamazepine or the CYP inhibitor ritonavir on the brain and plasma kinetics of [ 11 C]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 ( V T ) of [ 11 C]metoclopramide. CYP induction or inhibition had negligible impact on the plasma kinetics and metabolism of [ 11 C]metoclopramide. Moreover, carbamazepine neither impacted the brain kinetics nor V T of [ 11 C]metoclopramide ( p > 0.05). However, ritonavir significantly increased V T ( 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 [ 11 C]metoclopramide PET. This supports further use of [ 11 C]metoclopramide for studies in animals and patients treated with CYP inducers.
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