Cancer medicine · 2020
The underlying mechanisms of lorlatinib penetration across the blood-brain barrier and the distribution characteristics of lorlatinib in the brain.
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Chen Wei, Jin Dujia, Shi Yafei, Zhang Yujun, Zhou Haiyan, Li Guohui
Аннотация
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.
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.