Heterogeneous drug tissue binding in brain regions of rats, Alzheimer's patients and controls: impact on translational drug development

Sofia Gustafsson; Dag Sehlin; Erik Lampa; Margareta Hammarlund-Udenaes; Irena Loryan

doi:10.1038/s41598-019-41828-4

Heterogeneous drug tissue binding in brain regions of rats, Alzheimer's patients and controls: impact on translational drug development

Sci Rep. 2019 Mar 29;9(1):5308. doi: 10.1038/s41598-019-41828-4.

Authors

Sofia Gustafsson¹, Dag Sehlin², Erik Lampa³, Margareta Hammarlund-Udenaes¹, Irena Loryan⁴

Affiliations

¹ Translational PKPD Group, Department of Pharmaceutical Biosciences, Associate member of SciLifeLab, Uppsala University, Uppsala, Sweden.
² Molecular Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
³ Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
⁴ Translational PKPD Group, Department of Pharmaceutical Biosciences, Associate member of SciLifeLab, Uppsala University, Uppsala, Sweden. irena.loryan@farmbio.uu.se.

Abstract

For preclinical and clinical assessment of therapeutically relevant unbound, free, brain concentrations, the pharmacokinetic parameter fraction of unbound drug in brain (f_u,brain) is commonly used to compensate total drug concentrations for nonspecific brain tissue binding (BTB). As, homogenous BTB is assumed between species and in health and disease, rat BTB is routinely used. The impact of Alzheimer's disease (AD) on drug BTB in brain regions of interest (ROI), i.e., f_u,brain,ROI, is yet unclear. This study for the first time provides insight into regional drug BTB and the validity of employing rat f_u,brain,ROI as a surrogate of human BTB, by investigating five marketed drugs in post-mortem tissue from AD patients (n = 6) and age-matched controls (n = 6). Heterogeneous drug BTB was observed in all within group comparisons independent of disease and species. The findings oppose the assumption of uniform BTB, highlighting the need of case-by-case evaluation of f_u,brain,ROI in translational CNS research.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / diagnosis
Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism*
Amyloid beta-Peptides / metabolism
Animals
Brain / drug effects*
Brain / metabolism*
Case-Control Studies
Disease Models, Animal
Drug Development*
Drug Evaluation, Preclinical
Female
Humans
Male
Protein Binding
Rats
Tissue Distribution
Translational Research, Biomedical

Substances

Amyloid beta-Peptides