After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the molecular target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated. Here we investigated the efficacy and pharmacokinetics of PZQ in the Schistosoma mansoni mouse model to determine the key factors that drive its efficacy. Dose-response studies with racemic PZQ with or without addition of an irreversible pan-cytochrome P450 (CYP) inhibitor, 1-aminobenzotriazole (ABT), were performed. In addition, efficacy of PZQ in the presence of the CYP inducer, dexamethasone (DEX), was determined. Plasma samples were obtained by tail vein bleeding at 4 time points. The (R)-PZQ levels were determined using a LC-MS/MS method. Non-compartmental pharmacokinetic analysis was performed using PKsolver. In addition, experiments using an enhanced in vitro assay were conducted. We found that the use of ABT increased (R)-PZQ plasma exposures in the systemic circulation by ~10 to 20 fold but the latter were not predictive of efficacy. The use of DEX decreased plasma exposures of (R)-PZQ in the systemic circulation by ~10 fold without reducing efficacy. We extrapolated the (R)-PZQ concentrations in mouse portal vein / mesenteric veins from the systemic exposures and found that a free exposure of (R)-PZQ of ~ 20 μM*h in the portal vein was needed to obtain a worm burden reduction >60%. It is suggested that the high (R)-PZQ concentrations available before the hepatic first pass metabolism drive the efficacy against S. mansoni adult worms residing in the mesenteric veins. It is then possible that the current dosing regimen of 40 mg/kg in preventive chemotherapy programs may provide suboptimal concentrations in low-weight patients such as children, due to smaller total amounts of drug administered, and may consequently result in lower cure rates.

经过40多年的使用，吡喹酮（PZQ）仍然是治疗肠道和泌尿生殖道血吸虫病的首选药物。它的抗寄生虫活性主要存在于（R）-对映异构体中。迄今为止，分子靶标和药代动力学-药效关系都没有得到充分阐明。在这里，我们研究了曼氏血吸虫中PZQ的功效和药代动力学用小鼠模型确定驱动其功效的关键因素。进行了外消旋PZQ剂量反应研究，添加或不添加不可逆的泛细胞色素P450（CYP）抑制剂1-氨基苯并三唑（ABT）。此外，测定了在CYP诱导剂地塞米松（DEX）存在下PZQ的功效。在4个时间点通过尾静脉出血获得血浆样品。使用LC-MS / MS方法确定（R）-PZQ水平。使用PKsolver进行非房室药代动力学分析。另外，进行了使用增强的体外测定的实验。我们发现ABT的使用增加了（R）-PZQ在全身循环中的血浆暴露量约为10至20倍，但后者不能预测疗效。使用DEX可使全身循环中（R）-PZQ的血浆暴露降低约10倍，而不会降低功效。我们从全身暴露中推断出小鼠门静脉/肠系膜静脉中的（R）-PZQ浓度，发现门静脉中的（R）-PZQ自由暴露〜20μM* h才能降低蠕虫负担> 60％。建议在肝脏首过代谢之前可用的高（R）-PZQ浓度驱动对抗S的功效。曼索尼居住在肠系膜静脉中的成虫。因此，预防性化学疗法计划中目前的40 mg / kg给药方案可能会由于药物总量的减少而在低体重患者（例如儿童）中提供次优浓度，因此可能导致较低的治愈率。