Pharmacokinetics & Metabolism Division, Central Drug Research Institute, CSIR, Lucknow, India.
Eur J Pharm Sci. 2010 Oct 9;41(2):312-9. doi: 10.1016/j.ejps.2010.06.013. Epub 2010 Jul 3.
The pharmacokinetic data obtained in lower animals is of considerable importance in drug discovery and development. The objective of the present study was to generate in vitro and in vivo preclinical pharmacokinetic data of 99-357, a synthetic trioxane antimalarial, in rats and rabbits and to scale-up the data in order to apply for further studies. The pharmacokinetic profile of 99-357 was investigated after both intravenous and oral dose in rats and rabbits. Oral studies were carried out at three dose levels 6, 12 and 24mg/kg in rats while in rabbit only one dose level was selected. Both compartmental and non-compartmental approaches were used to calculate the pharmacokinetic parameters following intravenous and oral doses in both the species. The clearance in rat and rabbit was 45-57% and 60-67% respectively of hepatic blood flow. The plasma protein binding in rats was approximately 75%. In vitro studies showed high RBC partitioning and low to moderate hepatic clearance. Linearity was observed in terms of dose and AUCs suggesting linear pharmacokinetics at the dose levels studied in rats. The oral bioavailability of compound 99-357 in rat and rabbit at 12mg/kg dose level was comparable and 39% and 41% respectively.
在药物发现和开发中，从低等动物中获得的药代动力学数据具有重要意义。本研究的目的是生成合成三氧杂环己烷抗疟药 99-357 在大鼠和兔中的体外和体内临床前药代动力学数据，并对数据进行放大，以便申请进一步的研究。在大鼠和兔中分别静脉和口服给药后，研究了 99-357 的药代动力学特征。在大鼠中，口服研究在 6、12 和 24mg/kg 三个剂量水平进行，而在兔中仅选择一个剂量水平。在两种物种中，均采用房室模型和非房室模型方法来计算静脉和口服剂量后的药代动力学参数。大鼠和兔的清除率分别为肝血流量的 45-57%和 60-67%。大鼠的血浆蛋白结合率约为 75%。体外研究表明，红细胞分配较高，肝脏清除率较低至中等。在大鼠研究的剂量水平下，剂量和 AUC 均表现出线性关系，提示线性药代动力学。化合物 99-357 在大鼠和兔中的口服生物利用度在 12mg/kg 剂量水平相当，分别为 39%和 41%。
