Human Amyloid-β 40 Kinetics after Intravenous and Intracerebroventricular Injections and Calcitriol Treatment in Rats In Vivo

Drug Metab Dispos. 2020 Oct;48(10):944-955. doi: 10.1124/dmd.120.090886. Epub 2020 Aug 5.


Amyloid-β peptides of 40 and 42 amino acid lengths, which are synthesized in neurons and degraded in the brain and liver, have the potential to aggregate and form neuritic plaques in Alzheimer disease. The kinetics of human amyloid-β (hAβ) 40 were examined in the rat pursuant to intravenous and intracerebroventricular administration after pretreatment with calcitriol, the active vitamin D receptor ligand (6.4 nmol·kg-1 in 0.3 ml corn oil every other day for four intraperitoneal doses) to induce P-glycoprotein (P-gp) and enhance hAβ40 brain efflux. The interference of hAβ40 by media matrix that suppressed absorbance readings in the ELISA assay was circumvented with use of different calibration curves prepared in Standard Dilution Buffer, undiluted, 10-10,000 or 5-fold diluted plasma, or artificial cerebrospinal fluid. Simultaneous fitting of hAβ40 plasma and cerebrospinal fluid (CSF) data after intravenous and intracerebroventricular administration were described by catenary-mammillary models comprising of a central and two peripheral compartments, the brain, and one to four CSF compartments. The model with only one CSF compartment (model I) best fitted the intravenous data that showed a faster plasma decay t1/2 and slower equilibration between plasma and brain/CSF. Calcitriol induction increased the brain efflux rate constant, k41 (1.8-fold), at the blood-brain barrier when compared with the control group, as confirmed by the 2-fold (P < 0.05) increase in brain P-gp relative protein expression. SIGNIFICANCE STATEMENT: An accurate description of the kinetic behavior of human amyloid-β (hAβ) 40 is needed in defining the toxic peptide as a biomarker of Alzheimer disease. Modeling of hAβ40 data after intravenous and intracerebroventricular administration to the rat revealed an initially faster plasma half-life that reflected faster peripheral distribution but slower equilibration between plasma and brain/cerebrospinal fluid even with calcitriol pretreatment that increased P-glycoprotein protein expression and enhanced efflux clearance from brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / agonists
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Alzheimer Disease / blood
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / diagnosis
  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / pharmacokinetics*
  • Animals
  • Blood-Brain Barrier / metabolism*
  • Calcitriol / administration & dosage*
  • Humans
  • Injections, Intravenous
  • Injections, Intraventricular
  • Male
  • Models, Animal
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacokinetics*
  • Rats


  • ATP Binding Cassette Transporter, Subfamily B
  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • multidrug resistance protein 3
  • Calcitriol