The underlying mechanisms of lorlatinib penetration across the blood-brain barrier and the distribution characteristics of lorlatinib in the brain.
Aminopyridines
Animals
Biological Transport
Blood-Brain Barrier
/ drug effects
Cell Membrane Permeability
/ drug effects
Humans
Hypoxia
/ complications
Ischemia
/ drug therapy
Lactams
Lactams, Macrocyclic
/ pharmacokinetics
Male
Neuroblastoma
/ drug therapy
Pyrazoles
Rats
Rats, Sprague-Dawley
Reperfusion Injury
/ drug therapy
Tissue Distribution
Tumor Cells, Cultured
Crizotinib
Lorlatinib
SPP1
blood-brain barrier
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
05
02
2020
revised:
23
03
2020
accepted:
23
03
2020
pubmed:
30
4
2020
medline:
18
5
2021
entrez:
30
4
2020
Statut:
ppublish
Résumé
To clarify the distribution of lorlatinib in the brain and elucidate the molecular mechanisms of lorlatinib penetration across the blood-brain barrier (BBB). Cytological experiments were performed to investigate the growth inhibitory effect of lorlatinib on different cells (endothelial cells HUVEC, HMEC-1, and HCMEC/D3) and to investigate the protective effect of lorlatinib on neuronal cells after SH-SY5Y hypoxia/reoxygenation injury. Furthermore, rat brain tissue was sequenced, and the differentially expressed genes (secreted phosphoprotein 1 (SPP1), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), Claudin, ZO-1 and P-gp) in several different drug treatment groups were verified by Real-Time PCR. Lorlatinib brain distribution was predicted by physiologically based pharmacokinetics (PBPK). Lorlatinib and crizotinib both had inhibitory effects on endothelial cells, however lorlatinib inhibited the growth of HCMEC/D3 more efficaciously than crizotinib. In the SH-SY5Y hypoxia model, lorlatinib had a greater protective effect on nerve cell damage caused by hypoxia and reoxygenation than crizotinib. The expression of SPP1, VEGF, TGF-β, and Claudin in brain tissue was significantly downregulated after lorlatinib administration, and the expression level of early growth transcription factor 1 (Egr-1) was significantly increased. The PBPK model successfully described lorlatinib concentrations in blood and brain tissue in the mouse model and gave a brain tissue partition coefficient of 0.7. Lorlatinib can increase the permeability of the blood-brain barrier whereby we suggest its underlying working mechanism is related to downregulating SPP1, inhibiting VEGF, TGF-β, and Claudin subsequently reducing the number of tight junctions between BBB cells. Lorlatinib plays a protective role on injured nerve cells and does not change the amount of P-gp expression in brain tissue, which may be important for its ability to be efficacious across the BBB with a low incidence of resistance.
Identifiants
pubmed: 32347012
doi: 10.1002/cam4.3061
pmc: PMC7300403
doi:
Substances chimiques
Aminopyridines
0
Lactams
0
Lactams, Macrocyclic
0
Pyrazoles
0
lorlatinib
OSP71S83EU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4350-4359Informations de copyright
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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