Shen Baode, Shen Chengying, Zhu Weifeng, Yuan Hailong
Department of Pharmacy, Air Force Medical Center, PLA, Beijing 100142, China.
Key Lab of Modern Preparation of Traditional Chinese Medicine (TCM), Ministry of Education, Jiangxi University of TCM, Nanchang 330004, China.
Acta Pharm Sin B. 2021 Apr;11(4):978-988. doi: 10.1016/j.apsb.2021.02.015. Epub 2021 Feb 25.
In this study, self-discriminating hybrid nanocrystals was utilized to explore the biological fate of quercetin hybrid nanocrystals (QT-HNCs) with diameter around 280 nm (QT-HNCs-280) and 550 nm (QT-HNCs-550) following oral and intravenous administration and the contribution of integral nanocrystals to oral bioavailability enhancement of QT was estimated by comparing the absolute exposure of integral QT-HNCs and total QT in the liver. Results showed that QT-HNCs could reside as intact nanocrystals for as long as 48 h following oral and intravenous administration. A higher accumulation of integral QT-HNCs in liver and lung was observed for both oral and intravenous administration of QT-HNCs. The particle size affects the absorption and biodistribution of integral QT-HNCs and total QT. As compared to QT-HNCs-550, QT-HNCs-280 with smaller particle size is more easily absorbed, but dissolves faster , leading to higher distribution of QT (146.90 117.91 h·μg/mL) but lower accumulation of integral nanocrystals (6.8 2e10 15.27e10 h·[p/s]/[µW/cm²]) in liver following oral administration. Due to its slower dissolution and enhanced recognition by RES, QT-HNCs-550 with larger diameter shows higher liver distribution for both of QT (1015.80 h·μg/mL) and integral nanocrystals (259.63e10 h·[p/s]/[µW/cm²]) than those of QT-HNCs-280 (673.82 & 77.66e10 h·[p/s]/[µW/cm²]) following intravenous administration. The absolute exposure of integral QT-HNCs in liver following oral administration of QT-HNCs are 8.78% for QT-HNCs-280 and 5.88% for QT-HNCs-550, while the absolute exposure of total QT for QT-HNCs-280 and QT-HNCs-550 are 21.80% and 11.61%, respectively. Owing to imprecise quantification method, a surprisingly high contribution of integral QT-HNCs to oral bioavailability enhancement of QT (40.27% for QT-HNCs-280 and 50.65% for QT-HNCs-550) was obtained. These results revealed significant difference in absorption and biodistrbution between integral nanocrystals and overall drugs following oral and intravenous administration of QT-HNCs, and provided a meaningful reference for the contribution of integral nanocrystals to overall bioavailability enhancement.
在本研究中，利用自区分混合纳米晶体来探究直径约为280nm（QT-HNCs-280）和550nm（QT-HNCs-550）的槲皮素混合纳米晶体（QT-HNCs）经口服和静脉给药后的生物命运，并通过比较肝脏中完整QT-HNCs和总QT的绝对暴露量来评估完整纳米晶体对QT口服生物利用度提高的贡献。结果表明，QT-HNCs经口服和静脉给药后可作为完整纳米晶体存在长达48小时。口服和静脉注射QT-HNCs后，肝脏和肺中均观察到完整QT-HNCs的更高积累。粒径影响完整QT-HNCs和总QT的吸收和生物分布。与QT-HNCs-550相比，粒径较小的QT-HNCs-280更容易吸收，但溶解更快，导致口服给药后肝脏中QT的分布更高（146.90±117.91h·μg/mL），但完整纳米晶体的积累更低（6.82e10±15.27e10h·[p/s]/[µW/cm²]）。由于其溶解较慢且被RES识别增强，直径较大的QT-HNCs-550在静脉给药后，肝脏中QT（1015.80h·μg/mL）和完整纳米晶体（259.63e10h·[p/s]/[µW/cm²]）的分布均高于QT-HNCs-280（673.82和77.66e10h·[p/s]/[µW/cm²]）。口服QT-HNCs后，肝脏中完整QT-HNCs的绝对暴露量对于QT-HNCs-280为8.78%，对于QT-HNCs-550为5.88%，而QT-HNCs-280和QT-HNCs-550的总QT的绝对暴露量分别为21.80%和11.61%。由于定量方法不精确，获得了完整QT-HNCs对QT口服生物利用度提高的惊人高贡献（QT-HNCs-280为40.27%，QT-HNCs-550为50.65%）。这些结果揭示了口服和静脉注射QT-HNCs后完整纳米晶体与整体药物在吸收和生物分布上的显著差异，并为完整纳米晶体对整体生物利用度提高的贡献提供了有意义的参考。
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