Pharmacokinetic Modeling of (R)-[11C]verapamil to Measure the P-Glycoprotein Function in Nonhuman Primates

Lara Garcia Varela, David Vállez García, T Kakiuchi, Hiroyuki Ohba, S Nishiyama, T Tago, Philip H. Elsinga, Hideo Tsukada, Nicola Antonio Colabufo, Rudi Dierckx, Aren van Waarde, Jun Toyohara, Ronald Boellaard, Gert Luurtsema*

*Corresponding author for this work

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Abstract

(R)-[(11)C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[(11)C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[(11)C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[(11)C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[(11)C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[(11)C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[(11)C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (V(T)) and the efflux constant k(2) estimations were affected by the evaluated scan durations, whereas the influx constant K(1) estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain V(T) increased significantly up to 208% (p < 0.001) and K(1) up to 159% (p < 0.001) compared with baseline scans. The k(2) values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K(1), calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates
Original languageEnglish
Pages (from-to)416-428
Number of pages13
JournalMolecular pharmaceutics
Volume18
Issue number1
DOIs
Publication statusPublished - 4-Jan-2021

Keywords

  • P-GLYCOPROTEIN
  • VERAPAMIL
  • POSITRON-EMISSION-TOMOGRAPHY
  • Brain imaging
  • Non-human primates
  • PHARMACOKINETIC MODELING

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