Pandey Saurabh, Gautam Nagsen, Kushwaha Hari Narayan, Singh Shio Kumar
Pharmacokinetics and Metabolism Division, Central Drug Research Institute, UP, Lucknow, India.
School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
Biomed Chromatogr. 2016 Dec;30(12):2038-2043. doi: 10.1002/bmc.3782. Epub 2016 Aug 4.
The pharmacokinetic profile of 99/411, a novel anti-malarial drug, was established in rats (12 mg/kg of body weight) and monkeys (20 mg/kg of body weight). Following oral administration, the presence of 99/411 was rapidly determined in rat plasma, tissues, urine, feces and monkey plasma using a validated LC-MS/MS method. The tissue distribution studies in rats indicated that the drug was partially distributed in all major tissues and plasma, and peak concentration levels were achieved within 0.5-4 h. Area under the curve in different rat tissues and plasma was found in order of blood > lung > intestine > heart > muscle > brain > kidney > spleen > liver. The total recoveries (within 86 h) of 99/411 were <0.0017% and <0.08% in urine and feces, respectively. The peak plasma concentration was 3499 ng/mL in rats after ~2 h of oral administration and 697-767 ng/mL in monkeys after ~6 h of oral administration. No plasma accumulation was observed in both male and female monkeys, even after multiple dosing. The preclinical pharmacokinetic profile and tissue distribution data are expected to assist in future clinical explorations of 99/411 as a promising anti-malarial agent.
新型抗疟药物99/411的药代动力学特征在大鼠（12毫克/千克体重）和猴子（20毫克/千克体重）中得以确立。口服给药后，采用经过验证的液相色谱-串联质谱法在大鼠血浆、组织、尿液、粪便以及猴子血浆中迅速检测到了99/411的存在。大鼠的组织分布研究表明，该药物部分分布于所有主要组织和血浆中，在0.5至4小时内达到峰值浓度水平。在不同大鼠组织和血浆中测得的曲线下面积顺序为血液＞肺＞肠道＞心脏＞肌肉＞脑＞肾脏＞脾脏＞肝脏。99/411在尿液和粪便中的总回收率（86小时内）分别＜0.0017%和＜0.08%。大鼠口服给药约2小时后的血浆峰值浓度为3499纳克/毫升，猴子口服给药约6小时后的血浆峰值浓度为697至767纳克/毫升。即使多次给药，雄性和雌性猴子均未观察到血浆蓄积现象。临床前药代动力学特征和组织分布数据有望助力99/411作为一种有前景的抗疟药物的未来临床探索。
