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. 2020 Jun;9(12):4350-4359.
doi: 10.1002/cam4.3061. Epub 2020 Apr 28.

The underlying mechanisms of lorlatinib penetration across the blood-brain barrier and the distribution characteristics of lorlatinib in the brain

Wei Chen  1 , Dujia Jin  2 , Yafei Shi  1 , Yujun Zhang  1 , Haiyan Zhou  1 , Guohui Li  1
Affiliations

The underlying mechanisms of lorlatinib penetration across the blood-brain barrier and the distribution characteristics of lorlatinib in the brain

Wei Chen et al. Cancer Med. 2020 Jun.

Abstract

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-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).

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-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.

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-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.

Keywords: Crizotinib; Lorlatinib; SPP1; blood-brain barrier.

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Conflict of interest statement

There are no conflicting interests.

Figures

Figure 1
Figure 1
Inhibitive effects on growth of endothelial cells
Figure 2
Figure 2
Neuroprotective effects of lorlatinib and crizotinib on hypoxia injury in SY5Y cells
Figure 3
Figure 3
Effect on blood brain barrier (BBB) permeability
Figure 4
Figure 4
A, The number of differentially expressed genes in each group; B, Sequencing results of each administration group compared with that of the control group; C, The interaction pathway and target of SPP1 and the blood‐brain barrier. (C1: crizotinib single administration; C7: crizotinib repeated administration for 7 consecutive days; L1: lorlatinib single administration; L7: lorlatinib repeated administration for seven consecutive days; Con: control)
Figure 5
Figure 5
qPCR results of BBB‐related genes under the action of lorlatinib
Figure 6
Figure 6
qPCR results of BBB‐related genes under the action of lorlatinib and crizotinib
Figure 7
Figure 7
Concentration of lorlatinib in blood
Figure 8
Figure 8
Concentration of lorlatinib in brain
Figure 9
Figure 9
The underlying mechanisms of lorlatinib penetration across the blood‐brain barrier
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