PMID- 32347012
OWN - NLM
STAT- MEDLINE
DCOM- 20210517
LR  - 20211204
IS  - 2045-7634 (Electronic)
IS  - 2045-7634 (Linking)
VI  - 9
IP  - 12
DP  - 2020 Jun
TI  - The underlying mechanisms of lorlatinib penetration across the blood-brain 
      barrier and the distribution characteristics of lorlatinib in the brain.
PG  - 4350-4359
LID - 10.1002/cam4.3061 [doi]
AB  - OBJECTIVE: To clarify the distribution of lorlatinib in the brain and elucidate 
      the molecular mechanisms of lorlatinib penetration across the blood-brain barrier 
      (BBB). METHODS: 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-beta), 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). RESULTS: 
      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-beta, 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. CONCLUSION: 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-beta, 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.
CI  - (c) 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
FAU - Chen, Wei
AU  - Chen W
AUID- ORCID: 0000-0002-4015-6021
AD  - Department of Pharmacy, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Jin, Dujia
AU  - Jin D
AD  - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Shi, Yafei
AU  - Shi Y
AUID- ORCID: 0000-0002-2830-217X
AD  - Department of Pharmacy, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Zhang, Yujun
AU  - Zhang Y
AD  - Department of Pharmacy, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Zhou, Haiyan
AU  - Zhou H
AD  - Department of Pharmacy, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
FAU - Li, Guohui
AU  - Li G
AD  - Department of Pharmacy, National Cancer Center/National Clinical Research Center 
      for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union 
      Medical College, Beijing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200428
PL  - United States
TA  - Cancer Med
JT  - Cancer medicine
JID - 101595310
RN  - 0 (Aminopyridines)
RN  - 0 (Lactams)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Pyrazoles)
RN  - OSP71S83EU (lorlatinib)
SB  - IM
MH  - Aminopyridines
MH  - Animals
MH  - Biological Transport
MH  - Blood-Brain Barrier/drug effects/*metabolism
MH  - Cell Membrane Permeability/*drug effects
MH  - Humans
MH  - Hypoxia/*complications
MH  - Ischemia/*drug therapy/etiology/metabolism/pathology
MH  - Lactams
MH  - Lactams, Macrocyclic/pharmacokinetics/*pharmacology
MH  - Male
MH  - Neuroblastoma/*drug therapy/metabolism/pathology
MH  - Pyrazoles
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reperfusion Injury/*drug therapy/etiology/metabolism/pathology
MH  - Tissue Distribution
MH  - Tumor Cells, Cultured
PMC - PMC7300403
OTO - NOTNLM
OT  - Crizotinib
OT  - Lorlatinib
OT  - SPP1
OT  - blood-brain barrier
COIS- There are no conflicting interests.
EDAT- 2020/04/30 06:00
MHDA- 2021/05/18 06:00
PMCR- 2020/04/28
CRDT- 2020/04/30 06:00
PHST- 2020/02/05 00:00 [received]
PHST- 2020/03/23 00:00 [revised]
PHST- 2020/03/23 00:00 [accepted]
PHST- 2020/04/30 06:00 [pubmed]
PHST- 2021/05/18 06:00 [medline]
PHST- 2020/04/30 06:00 [entrez]
PHST- 2020/04/28 00:00 [pmc-release]
AID - CAM43061 [pii]
AID - 10.1002/cam4.3061 [doi]
PST - ppublish
SO  - Cancer Med. 2020 Jun;9(12):4350-4359. doi: 10.1002/cam4.3061. Epub 2020 Apr 28.