Human Amyloid-β40 Kinetics after Intravenous and Intracerebroventricular Injections and Calcitriol Treatment in Rats
H Benson Peng1, Keumhan Noh1, Sophie R Pan1
1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (H.B.P., K.N., K.S.P.) and InterVivo Solutions Inc., Mississauga, Ontario, Canada (S.R.P., V.S., S.S., A.T., I.A.M.d.L.).
Summary
Investigating human amyloid-β (hAβ) 40 kinetics in rats revealed calcitriol enhances brain efflux by increasing P-glycoprotein. This study models hAβ40 transport, crucial for Alzheimer
Area of Science:
- Neuroscience
- Pharmacokinetics
- Biochemistry
Background:
- Amyloid-β (Aβ) peptides, particularly Aβ40 and Aβ42, are implicated in Alzheimer disease pathogenesis due to their aggregation into neuritic plaques.
- Understanding the brain transport and clearance kinetics of Aβ peptides is crucial for developing effective therapeutic strategies and diagnostic biomarkers for Alzheimer disease.
Purpose of the Study:
- To investigate the pharmacokinetic behavior of human amyloid-β 40 (hAβ40) in rats following intravenous and intracerebroventricular administration.
- To evaluate the effect of calcitriol, a vitamin D receptor ligand, on hAβ40 brain efflux by modulating P-glycoprotein (P-gp) expression and activity.
Main Methods:
- Administered hAβ40 intravenously and intracerebroventricularly to rats, with a subset pretreated with calcitriol to induce P-gp.
- Utilized modified ELISA assays with specific calibration curves to accurately quantify hAβ40 in plasma and cerebrospinal fluid (CSF), overcoming matrix interference.
- Employed catenary-mammillary pharmacokinetic models to simultaneously fit plasma and CSF data, analyzing distribution and elimination kinetics.
Main Results:
- Calcitriol pretreatment significantly increased the brain efflux rate constant (k41) of hAβ40 by 1.8-fold at the blood-brain barrier.
- Confirmed a 2-fold increase in brain P-gp relative protein expression in calcitriol-treated rats, correlating with enhanced hAβ40 efflux.
- Pharmacokinetic modeling indicated an initial faster plasma half-life for hAβ40, suggesting rapid peripheral distribution, but slower equilibration between plasma and the brain/CSF compartments.
Conclusions:
- Calcitriol effectively enhances hAβ40 efflux from the brain by upregulating P-gp expression at the blood-brain barrier.
- The developed pharmacokinetic models provide an accurate description of hAβ40 kinetic behavior in vivo.
- These findings highlight the potential of modulating P-gp activity as a strategy to improve brain clearance of amyloid-β peptides in Alzheimer disease.
