Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects

The antiemetic and gastroprokinetic drug metoclopramide is a weak substrate of the blood-brain barrier (BBB) efflux transporter P-gp and displays central nervous system (CNS) side effects (i.e., extrapyramidal symptoms and tardive dyskinesia) caused by dopamine D₂ receptor blockade in the basal ganglia. These side effects occur with a higher incidence in elderly people. We used positron emission tomography to assess the brain distribution of [¹¹ C]metoclopramide in young (n = 11, 26 ± 3 years) and elderly (n = 7, 68 ± 9 years) healthy men both after administration of a microdose (9 ± 7 µg) and a microdose co-injected with a therapeutic dose of unlabeled metoclopramide (10 mg). For both doses, elderly subjects had a significantly higher total volume of distribution (V_T ) of [¹¹ C]metoclopramide in the basal ganglia than young subjects (microdose: +26%, therapeutic dose: +41%). Increases in V_T (= K₁ /k₂ ) were caused by significant decreases in the transfer rate constant of [¹¹ C]metoclopramide from brain into plasma (k₂ , microdose: -18%, therapeutic dose: -30%), whereas the distributional clearance from plasma into brain (K₁ ) remained unaltered. This reduction in the clearance of [¹¹ C]metoclopramide (k₂ ) from the brains of elderly subjects may be caused by an age-related decrease in the activity of P-gp at the BBB and may contribute to the higher incidence of CNS side effects of metoclopramide in the aged population. Our data suggest that an age-associated decrease in the clearance properties of the BBB may modulate the CNS effects or side effects of clinically used P-gp substrates.