Yang Li, Yu Ying-Li, Cheng Li-Yuan, Zhang Pan-Yang, Zhang Yue, Zhou Kun
Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
Tianjin Key Laboratory of Chinese medicine Pharmacology, Tianjin 301617, China.
ACS Omega. 2020 Mar 24;5(13):7307-7315. doi: 10.1021/acsomega.9b04153. eCollection 2020 Apr 7.
Psoralen is a furanocoumarin compound found in many herb medicines and is claimed to contribute to the hepatotoxicity caused by lots of traditional Chinese medicine. So far, there has been no research on the differences in pharmacokinetics of single and repeated dosing of psoralen. Moreover, the research on the cumulative toxicity of low concentration and long-term administration on cells has not been reported. Therefore, this study investigated the pharmacokinetic differences and the accumulated cytotoxicity of psoralen from repeated administration. The study found that after single or repeated administration of psoralen for 3 months at various dosages (14, 28, and 56 mg/kg), the pharmacokinetic parameters of female rats between single dose and repeated dose administration are totally different. Compared with a single administration, multiple administrations increased psoralen's in vivo exposure, prolonged the peak time, prolonged the half-life of the drug, reduced the drug clearance rate, and prolonged the drug's stay in the body. HepG2 cells were exposed to low doses (5, 10, 20, or 40 μM) of psoralen for 1, 2, 3, or 4 days. A 20 and 40 μM dose of psoralen did not induced cell death in the 1st day but significantly decreased the cell viability at the 3rd and 4th day of repeated administration, respectively. In addition, multiple administrations of psoralen decreased cell viability due to G2 arrest.
补骨脂素是一种存在于多种草药中的呋喃香豆素化合物，据称它会导致许多中药引起肝毒性。到目前为止，尚未有关于补骨脂素单次给药和重复给药药代动力学差异的研究。此外，关于低浓度长期给药对细胞的累积毒性研究也未见报道。因此，本研究调查了补骨脂素重复给药后的药代动力学差异和累积细胞毒性。研究发现，在以不同剂量（14、28和56mg/kg）单次或重复给药补骨脂素3个月后，雌性大鼠单次给药和重复给药之间的药代动力学参数完全不同。与单次给药相比，多次给药增加了补骨脂素的体内暴露量，延长了达峰时间，延长了药物半衰期，降低了药物清除率，并延长了药物在体内的停留时间。将HepG2细胞暴露于低剂量（5、10、20或40μM）的补骨脂素中1、2、3或4天。20和40μM剂量的补骨脂素在第1天未诱导细胞死亡，但在重复给药的第3天和第4天分别显著降低了细胞活力。此外，多次给药补骨脂素由于G2期阻滞而降低了细胞活力。
