Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments.
Addressing the oxamniquine in vitro-in vivo paradox to facilitate a new generation of anti-schistosome treatments.
复制标题
DOI：
10.1016/j.ijpddr.2023.01.003
复制
发表时间：
2023-04
影响因子：
4
通讯作者：
Cameron, Michael D.
中科院分区：
文献类型：
--
作者：
Toth, Katalin;Alwan, Sevan;Khan, Susan;McHardy, Stanton F.;LoVerde, Philip T.;Cameron, Michael D.
抗血吸虫药物奥沙米奎因(OXA)需要被寄生虫内的磺基转移酶激活才能杀死。对OXA的药代动力学/药效学(PK/PD)关系的研究发现，OXA存在体内外矛盾，其临床最大血药浓度比体外血吸虫杀灭的有效浓度低5-10倍。寄生虫驻留在肠道和肝脏之间的血管系统中，并对PK数据进行建模，以确定与体外研究相吻合的门静脉浓度，并解释了所需的人类剂量。在电子计算机模型中，用来预测小鼠的剂量，以概括OXA门脉浓度和时间进程的人类条件。后续的PK研究在小鼠身上证实，在醋酸盐缓冲液中配制的50-100 mg/kg口服剂量的OXA概括了患者中常见的20-40 mg/kg剂量。通过代谢和排泄到胆汁中，OXA被迅速清除。野生型和P-gp外排转运蛋白基因敲除小鼠的OXA吸光度和组织分布相似。一种改进的OXA类似物被证明结合了体外疗效数据和门静脉浓度，该类似物已被证明可以杀死曼氏血吸虫、血吸虫和日本血吸虫，而OXA只对曼氏血吸虫有效。第二代OXA类似物应优化体外杀伤和理化性质，通过良好的溶解性、渗透性和最低的肠道代谢，通过快速口服吸收实现高门脉浓度。门静脉OXA浓度可预测有效剂量。小鼠口服50-100 mg/kg的OXA概括了与生理相关的人类治疗条件。PK模型成功预测了体内血药浓度。清除胆汁中的OXA和鉴定两个新的OXA葡萄糖醛酸苷是新的清除机制。OXA是一种中枢神经系统渗透剂，可能会导致限量镇静、头晕和头痛。
The antischistosomal drug oxamniquine, OXA, requires activation by a sulfotransferase within the parasitic worm to enable killing. Examination of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for OXA identified an in vitro-in vivo paradox with the maximal clinical plasma concentrations five-to ten-times lower than the efficacious concentration for in vitro schistosomal killing. The parasite resides in the vasculature between the intestine and the liver, and modeling the PK data to determine portal concentrations fits with in vitro studies and explains the required human dose. In silico models were used to predict murine dosing to recapitulate human conditions for OXA portal concentration and time course. Follow-up PK studies verified in mice that a 50–100 mg/kg oral gavage dose of OXA formulated in acetate buffer recapitulates the 20–40 mg/kg dose common in patients. OXA was rapidly cleared through a combination of metabolism and excretion into bile. OXA absorbance and tissue distribution were similar in wild-type and P-gp efflux transporter knockout mice. The incorporation of in vitro efficacy data and portal concentration was demonstrated for an improved OXA-inspired analog that has been shown to kill S. mansoni, S. haematobium, and S. japonicum, whereas OXA is only effective against S. mansoni. Second-generation OXA analogs should optimize both in vitro killing and physiochemical properties to achieve high portal concentration via rapid oral absorption, facilitated by favorable solubility, permeability, and minimal intestinal metabolism. Portal OXA concentration predicts the efficacious dose. A 50–100 mg/kg oral dose of OXA in mice recapitulates physiologically relevant human treatment conditions. PK modeling successfully predicted in vivo plasma concentrations. Elimination of OXA in bile and the identification of two new OXA glucuronides are reported as new clearance mechanisms. OXA is CNS penetrant, which may contribute to dose-limiting sedation, dizziness, and headaches.
登录
查看更多内容
DOI：
10.1208/ps040425
发表时间：
2002-01-01
期刊：
AAPS PHARMSCI
影响因子：
--
作者：
Ito, K;Chiba, K;Sugiyama, Y
通讯作者：
Sugiyama, Y
DOI：
10.1590/s0074-02762011000200006
发表时间：
2011-03-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Couto, Flávia FB;Coelho, Paulo Marcos Z;Mattos, Ana Carolina A
通讯作者：
Mattos, Ana Carolina A
影响因子：
3.8
作者：
Mnkugwe RH;Minzi O;Kinung'hi S;Kamuhabwa A;Aklillu E
通讯作者：
Aklillu E
DOI：
10.1080/00034983.1976.11687128
发表时间：
1976-01-01
影响因子：
--
作者：
KAYE, B;WOOLHOUSE, NM
通讯作者：
WOOLHOUSE, NM
DOI：
10.4269/ajtmh.2006.74.342
发表时间：
2006-02-01
影响因子：
3.3
作者：
Alonso, D;Muñoz, J;Corachan, M
通讯作者：
Corachan, M