Vennerstrom J L, Ager A L, Andersen S L, Grace J M, Wongpanich V, Angerhofer C K, Hu J K, Wesche D L
College of Pharmacy, University of Nebraska Medical Center, Omaha 68198-6025, USA.
Am J Trop Med Hyg. 2000 May;62(5):573-8. doi: 10.4269/ajtmh.2000.62.573.
The antimalarial peroxide, dispiro-1,2,4,5-tetraoxane WR 148999, was synergistic with chloroquine, quinine, mefloquine, and artemisinin against both D6 and W2 clones of Plasmodium falciparum. In consideration of the contrasting antagonism between artemisinin and chloroquine, these drug combination data imply that WR 148999 and artemisinin may not share a common mechanism of action. For Plasmodium berghei-infected mice given oral, subcutaneous, and intraperitoneal doses of WR 148999 ranging from 2 to 1024 mg/kg in the Thompson test, median survival times were 8.8, 11.8, and 27.5 days, respectively, compared to 8 days for control animals. Using subcutaneous administration, WR 148999 had a considerably longer duration of action than did artemisinin against P. berghei. WR 148999 did not significantly inhibit cytochrome P450 isozymes CYP 2C9, 2C19, 2D6, 2E1, or 3A4 (IC50 >500 microM) but did inhibit CYP 1A2 with an IC50 value of 36 microM, suggesting that WR 148999 may be metabolized by the latter CYP isozyme. These results combined with previous observations that formulation strategies and incorporation of polar functional groups in a series of WR 148999 analogs both failed to enhance tetraoxane oral antimalarial activity suggest that oral bioavailability of tetraoxane WR 148999 is more likely a function of extensive first-pass metabolism rather than solubility-limited dissolution.
抗疟过氧化物双螺-1,2,4,5-四氧杂环辛烷WR 148999与氯喹、奎宁、甲氟喹和青蒿素联合使用时，对恶性疟原虫的D6和W2克隆均具有协同作用。鉴于青蒿素与氯喹之间存在明显的拮抗作用，这些药物联合使用的数据表明，WR 148999和青蒿素可能不具有共同的作用机制。在汤普森试验中，给感染伯氏疟原虫的小鼠口服、皮下和腹腔注射剂量范围为2至1024 mg/kg的WR 148999，其平均存活时间分别为8.8天、11.8天和27.5天，而对照动物为8天。采用皮下给药时，WR 148999对伯氏疟原虫的作用持续时间比青蒿素长得多。WR 148999对细胞色素P450同工酶CYP 2C9、2C19、2D6、2E1或3A4没有显著抑制作用（IC50>500 microM），但对CYP 1A2有抑制作用，IC50值为36 microM，这表明WR 148999可能由后一种CYP同工酶代谢。这些结果与之前的观察结果相结合，即在一系列WR 148999类似物中，制剂策略和极性官能团的引入均未能提高四氧杂环辛烷的口服抗疟活性，这表明四氧杂环辛烷WR 148999的口服生物利用度更可能是广泛首过代谢的结果，而不是溶解度限制溶解的结果。
