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

Abstract

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 (extrapyramidal symptoms, tardive dyskinesia), which occur with a higher incidence in elderly people. WHAT QUESTION DID THIS STUDY ADDRESS?  We performed [ 11 C]metoclopramide positron emission tomography scans in young and elderly healthy men, both after administration of a microdose and therapeutic dose of metoclopramide, to investigate whether differences in brain distribution of metoclopramide may explain its CNS side effects.

Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [11C]Metoclopramide

“…The aim of this study was to measure the biodistribution and organ dosimetry of [ 11 C]metoclopramide, a new PET tracer for assessing the activity of P-gp at the BBB [8][9][10][11][12].…”

“…In good agreement with previous studies, we found that the majority of the administered radioactivity was taken up into the liver with approximately 12 % of the injected dose being excreted into the urine over the short time duration of the PET examination (approximately 70 min). The major radiolabeled metabolite of [ 11 C]metoclopramide in human plasma was identified in our previously published study as the corresponding 11 C-labeled N-O-glucuronide [11]. As it has been shown that the N-O-glucuronide was also a major metabolite of metoclopramide in the urine [17], it can be assumed that part of the radioactivity excreted into urine was in the form of the 11 C-labeled N-Oglucuronide of [ 11 C]metoclopramide.…”

“…Positron emission tomography (PET) with radiolabeled Pgp substrates, such as racemic [ 11 C]verapamil [2,3], (R)-[ 11 C]verapamil [4,5] and [ 11 C]N-desmethyl-loperamide [6], has been proposed as a useful tool to measure P-gp activity at the BBB in health and disease. However, these radiotracers are very efficiently transported by P-gp at the BBB ("avid" P-gp substrates) leading to very low brain uptake and limited sensitivity to measure disease-induced alterations in P-gp activity at the BBB [7].…”

“…[ 11 C]Metoclopramide is a weak P-gp substrate, which shows higher baseline brain uptake than previously described "avid" P-gp substrates and may thus possess better sensitivity to measure P-gp activity at the BBB, in particular in conditions in which the activity of P-gp is upregulated (e.g. drug-resistant epilepsy) [8][9][10][11][12].…”

Influence of Cation Transporters (OCTs and MATEs) on the Renal and Hepatobiliary Disposition of [11C]Metoclopramide in Mice

“…One major metabolic pathway of metoclopramide is oxidation by CYP2D6 in the liver followed by conjugation (10,11). An N-O-glucuronide has been identified as the major metoclopramide metabolite in human urine and plasma (12,13). Previous studies have provided evidence for non-linear pharmacokinetics of metoclopramide in rats and humans, suggesting a role of saturable mechanisms in its clearance (9,(14)(15)(16).…”