Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts
Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts
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DOI：
10.1128/aac.00535-20
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发表时间：
2020-09-01
影响因子：
4.9
通讯作者：
Carruthers, Vern B.
中科院分区：
文献类型：
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作者：
Doggett, J. Stone;Schultz, Tracey;Carruthers, Vern B.
弓形虫病对免疫功能低下的人和发育中的胎儿来说是一种潜在的致命感染。目前用于弓形虫病的药物具有干扰治疗和预防方案的高不良反应率。类内毒素喹诺酮类药物（ELQs）在体外、急性和潜伏感染的动物模型中均能有效抑制弓形虫的增殖。特别是，发现ELQ-316口服对小鼠急性弓形虫病有效，并且对T.弓形虫细胞色素B高于人细胞色素B。尽管其口服有效，但ELQ-316的高结晶度限制了口服吸收、血浆浓度和治疗潜力。创建ELQ-316的碳酸酯前药ELQ-334以降低结晶度并增加口服生物利用度，这导致ELQ-316的最大血浆浓度（C-max）和曲线下面积（AUC）增加6倍。当作为ELQ-334施用时，ELQ-316的生物利用度增加，导致对抗急性弓形虫病的功效大于等效剂量的ELQ-316的功效，并且对抗潜伏性弓形虫病的功效与腹膜内施用的ELQ-316的功效相似。用碳酸酯前药治疗是克服ELQ用于治疗弓形虫病的有限口服生物利用度的成功策略。
Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for T. gondii cytochrome b over human cytochrome b. Despite its oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations, and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a 6-fold increase in both the maximum plasma concentration (C-max) and the area under the curve (AUC) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in efficacy against acute toxoplasmosis greater than that of an equivalent dose of ELQ-316 and had efficacy against latent toxoplasmosis similar to that of ELQ-316 administered intraperitoneally. Treatment with carbonate ester prodrugs is a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.