Makita-Suzuki Keiko, Kakinuma Chihaya, Inomata Akira, Shimada Yasuhiro, Hara Takefumi, Yao Takashi
Pharmaceutical & Healthcare Research Laboratories, FUJIFILM Corporation, 577 Ushijima, Kaisei-machi, Ashigarakami-gun, Kanagawa 258-8577, Japan.
Department of Human Pathology, Juntendo University Faculty of Medicine, 1-1-19 Bunkyo-ku, Tokyo 113-8421, Japan.
J Toxicol Pathol. 2020 Jan;33(1):1-9. doi: 10.1293/tox.2019-0029. Epub 2019 Sep 12.
Although several liposomal drugs, including liposomal doxorubicin, have been approved, the etiology of the pathological responses caused by their physicochemical properties remains unknown. Herein, we investigated the pathological changes in the liver and the gallbladder of dogs following a single injection of liposomal doxorubicin (1 or 2.5 mg/kg) or an empty liposomal formulation (i.e., liposomal formulation without doxorubicin, ca. 21 mg/kg as lipid content). Injection of liposomal doxorubicin or the empty liposomal formulation induced hemorrhagic changes in the liver and the gallbladder. These changes were accompanied by minimal cellular infiltration with no obvious changes in the blood vessels. As there were no differences in the incidence and severity of hemorrhage between the groups administered comparable amounts of total lipid, the physicochemical properties of the liposomal formulation rather than an active pharmacological ingredient, doxorubicin, were associated with the hemorrhagic changes. Furthermore, decreased cytoplasmic granules with low electron density in mast cells beneath the endothelium of the hepatic vein were observed in the liver of dogs treated with liposomal doxorubicin or empty liposomal formulation. Injection of compound 48/80, a histamine releaser induced comparable hemorrhage in dogs, implying that hemorrhage caused by injection of liposomal doxorubicin or the empty liposomal formulation could be attributed to the histamine released from mast cells. The absence of similar hemorrhagic lesions in other species commonly used in toxicology studies (i.e., rats and monkeys), as well as humans, is due to the lack of mast cells beneath the endothelium of the hepatic vein in these species.
尽管包括脂质体阿霉素在内的几种脂质体药物已获批准，但其理化性质所引起的病理反应的病因仍不清楚。在此，我们研究了单次注射脂质体阿霉素（1或2.5mg/kg）或空脂质体制剂（即不含阿霉素的脂质体制剂，脂质含量约为21mg/kg）后犬肝脏和胆囊的病理变化。注射脂质体阿霉素或空脂质体制剂会引起肝脏和胆囊的出血性变化。这些变化伴有最小程度的细胞浸润，血管无明显变化。由于给予相当量总脂质的组之间出血的发生率和严重程度没有差异，脂质体制剂的理化性质而非活性药理成分阿霉素与出血性变化有关。此外，在用脂质体阿霉素或空脂质体制剂治疗的犬的肝脏中，观察到肝静脉内皮下方肥大细胞中低电子密度的细胞质颗粒减少。注射组胺释放剂化合物48/80在犬中引起类似的出血，这意味着注射脂质体阿霉素或空脂质体制剂引起的出血可能归因于肥大细胞释放的组胺。在毒理学研究中常用的其他物种（即大鼠和猴子）以及人类中没有类似的出血性病变，是因为这些物种肝静脉内皮下方缺乏肥大细胞。
