Sallam Hatem, El-Serafi Ahmed T, Filipski Elisabeth, Terelius Ylva, Lévi Francis, Hassan Moustapha
Experimental Cancer Medicine, Department of Laboratory Medicine, Karolinska Institutet , Stockholm , Sweden .
Chronobiol Int. 2015 Jun;32(5):608-14. doi: 10.3109/07420528.2015.1022782. Epub 2015 May 4.
Roscovitine is a selective Cdk-inhibitor that is under investigation in phase II clinical trials under several conditions, including chemotherapy. Tumor growth inhibition has been previously shown to be affected by the dosing time of roscovitine in a Glasgow osteosarcoma xenograft mouse model. In the current study, we examined the effect of dose timing on the pharmacokinetics, biodistribution and metabolism of this drug in different organs in B6D2F1 mice. The drug was orally administered at resting (ZT3) or activity time of the mice (ZT19) at a dose of 300 mg/kg. Plasma and organs were removed at serial time points (10, 20 and 30 min; 1, 2, 4, 6, 8, 12 and 24 h) after the administration. Roscovitine and its carboxylic metabolite concentrations were analyzed using HPLC-UV, and pharmacokinetic parameters were calculated in different organs. We found that systemic exposure to roscovitine was 38% higher when dosing at ZT3, and elimination half-life was double compared to when dosing at ZT19. Higher organ concentrations expressed as (organ/plasma) ratio were observed when dosing at ZT3 in the kidney (180%), adipose tissue (188%), testis (132%) and lungs (112%), while the liver exposure to roscovitine was 120% higher after dosing at ZT19. The metabolic ratio was approximately 23% higher at ZT19, while the intrinsic clearance (CLint) was approximately 67% higher at ZT19, indicating faster and more efficient metabolism. These differences may be caused by circadian differences in the absorption, distribution, metabolism and excretion processes governing roscovitine disposition in the mice. In this article, we describe for the first time the chronobiodistribution of roscovitine in the mouse and the contribution of the dosing time to the variability of its metabolism. Our results may help in designing better dosing schedules of roscovitine in clinical trials.
罗斯考维汀是一种选择性细胞周期蛋白依赖性激酶（Cdk）抑制剂，目前正在多项条件下进行II期临床试验研究，包括化疗。先前在格拉斯哥骨肉瘤异种移植小鼠模型中已表明，肿瘤生长抑制受罗斯考维汀给药时间的影响。在本研究中，我们考察了给药时间对该药物在B6D2F1小鼠不同器官中的药代动力学、生物分布和代谢的影响。以300mg/kg的剂量在小鼠休息时（ZT3）或活动时（ZT19）口服给药。给药后在连续时间点（10、20和30分钟；1、2、4、6、8、12和24小时）采集血浆和器官。使用高效液相色谱-紫外检测法分析罗斯考维汀及其羧酸代谢物的浓度，并计算不同器官的药代动力学参数。我们发现，在ZT3给药时，罗斯考维汀的全身暴露量高38%，消除半衰期是在ZT19给药时的两倍。以（器官/血浆）比值表示，在ZT3给药时，肾脏（180%）、脂肪组织（188%）、睾丸（132%）和肺（112%）中观察到较高的器官浓度，而在ZT19给药后肝脏对罗斯考维汀的暴露量高120%。代谢率在ZT19时约高23%，而内在清除率（CLint）在ZT19时约高67%，表明代谢更快且更有效。这些差异可能是由小鼠体内罗斯考维汀处置过程中吸收、分布、代谢和排泄的昼夜差异引起的。在本文中，我们首次描述了罗斯考维汀在小鼠体内的时辰生物分布以及给药时间对其代谢变异性的影响。我们的结果可能有助于在临床试验中设计更好的罗斯考维汀给药方案。
