P-Glycoprotein-Mediated Efflux Reduces the In Vivo Efficacy of a Therapeutic Targeting the Gastrointestinal Parasite Cryptosporidium
P-Glycoprotein-Mediated Efflux Reduces the In Vivo Efficacy of a Therapeutic Targeting the Gastrointestinal Parasite Cryptosporidium
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DOI：
10.1093/infdis/jiz269
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发表时间：
2019-10-01
影响因子：
6.4
通讯作者：
Van Voorhis, Wesley C.
中科院分区：
文献类型：
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作者：
Arnold, Samuel L. M.;Choi, Ryan;Van Voorhis, Wesley C.
最近的研究表明，隐孢子虫感染对营养不良的儿童和免疫功能低下的个人的生活造成了负担。治疗选择仍然有限，目前正在努力开发新的治疗方法。然而，关于新的抗隐孢子虫治疗剂的理想药代动力学特征存在未解决的问题。具体来说，药物开发者是否应该优化治疗方法和配方，以增加药物在胃肠道、肠上皮细胞或体循环中的暴露？此外，研究人员应该如何解释数据表明，他们的治疗是一个药物外排转运底物？体内药物转运蛋白介导的疗效改变在多个疾病领域得到了广泛认可，但肠道转运蛋白对肠道疾病治疗疗效的影响尚未确定。使用多种体外模型和隐孢子虫感染的小鼠模型，我们表征了P-糖蛋白流出对碰撞激酶抑制剂药代动力学和功效的影响。我们的研究结果表明，P-糖蛋白减少了碰撞激酶抑制剂肠上皮细胞的暴露，导致对隐孢子虫的体内疗效降低。此外，隐孢子虫感染的中空纤维模型复制了P-糖蛋白对抗隐孢子虫功效的体内影响。总之，在优化靶向胃肠道上皮或胃肠道上皮感染的候选药物时，药物开发人员应考虑主动外排转运蛋白对疗效的不利影响。
Recent studies have illustrated the burden Cryptosporidium infection places on the lives of malnourished children and immunocompromised individuals. Treatment options remain limited, and efforts to develop a new therapeutic are currently underway. However, there are unresolved questions about the ideal pharmacokinetic characteristics of new anti-Cryptosporidium therapeutics. Specifically, should drug developers optimize therapeutics and formulations to increase drug exposure in the gastrointestinal lumen, enterocytes, or systemic circulation? Furthermore, how should researchers interpret data suggesting their therapeutic is a drug efflux transporter substrate? In vivo drug transporter-mediated alterations in efficacy are well recognized in multiple disease areas, but the impact of intestinal transporters on therapeutic efficacy against enteric diseases has not been established. Using multiple in vitro models and a mouse model of Cryptosporidium infection, we characterized the effect of P-glycoprotein efflux on bumped kinase inhibitor pharmacokinetics and efficacy. Our results demonstrated P-glycoprotein decreases bumped kinase inhibitor enterocyte exposure, resulting in reduced in vivo efficacy against Cryptosporidium. Furthermore, a hollow fiber model of Cryptosporidium infection replicated the in vivo impact of P-glycoprotein on anti-Cryptosporidium efficacy. In conclusion, when optimizing drug candidates targeting the gastrointestinal epithelium or gastrointestinal epithelial infections, drug developers should consider the adverse impact of active efflux transporters on efficacy.