Hui Yu-hua, Huang Naijia Helen, Ebbert Lewis, Bina Holly, Chiang Alan, Maples Carma, Pritt Michael, Kern Tom, Patel Nita
Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
J Pharmacol Toxicol Methods. 2007 Sep-Oct;56(2):256-64. doi: 10.1016/j.vascn.2007.05.006. Epub 2007 Jun 2.
The evaluation of drug disposition properties of chemical entities in drug discovery research typically involves the conduct of pharmacokinetic studies in rodents that requires blood sampling over several time points, preferably without disrupting the physiological status of the animals. Several blood withdrawal methods have been employed throughout the industry, yet these methods have not been comprehensively evaluated with regard to their effects on pharmacokinetic profiles of the drug investigated to recommend best practices.
In this paper, the pharmacokinetics of six marketed drugs from four distinct therapeutic classes were compared using tail-vein, femoral-artery cannula-, and retro-orbital sinus bleeding techniques. The marketed drugs used in these studies were pentoxifylline, gemfibrozil, glipizide, methotrexate, clonidine, and fluoxetine.
Following oral administration, peak plasma concentration (C(max)), and area under the curve (AUC(0-24)) values for all compounds were not significantly different with the tail-vein method when compared to cannula- or retro-orbital sinus bleeding, except for fluoxetine and gemfibrozil for which minor, but statistically significant differences were observed. The effect of arterial versus venous tail-bleeding on the pharmacokinetics of pentoxifylline indicated no statistical differences in either C(max) or AUC(0-24) values. However, for fluoxetine, higher exposures were observed with tail arterial than venous sampling (2-fold with respect to C(max) and 1.7-fold with respect to AUC(0-24), p<0.05).
The observed differences with fluoxetine may be due to its pharmacological effects on thermoregulatory responses that influence tail blood flow, a hypothesis that remains to be tested. Based on these observations, we recommend the tail-bleeding technique for pharmacology or toxicology exposure and F% studies, particularly in early discovery work. Retro-orbital bleeding is controversial and is no longer considered a humane method. Cannula-bleeding, especially coupled with automated blood-collection techniques, has become the most efficient way for pharmaceutical industry to perform rat bioavailability studies.
在药物发现研究中，对化学实体的药物处置特性进行评估通常需要在啮齿动物中开展药代动力学研究，这要求在多个时间点采集血样，最好不干扰动物的生理状态。整个行业采用了多种采血方法，但这些方法对所研究药物药代动力学特征的影响尚未得到全面评估，以推荐最佳实践方法。
本文使用尾静脉、股动脉插管和眶后窦出血技术比较了来自四个不同治疗类别的六种上市药物的药代动力学。这些研究中使用的上市药物为己酮可可碱、吉非贝齐、格列吡嗪、甲氨蝶呤、可乐定和氟西汀。
口服给药后，与插管或眶后窦出血相比，所有化合物的血浆峰浓度（C(max)）和曲线下面积（AUC(0 - 24)）值采用尾静脉法时无显著差异，但氟西汀和吉非贝齐观察到轻微但具有统计学意义的差异。己酮可可碱动脉与静脉尾端采血对药代动力学的影响表明，C(max)或AUC(0 - 24)值均无统计学差异。然而，对于氟西汀，尾动脉采样比静脉采样观察到更高的暴露量（C(max)方面高2倍，AUC(0 - 24)方面高1.7倍，p<0.05）。
观察到的氟西汀差异可能是由于其对影响尾血流量的体温调节反应的药理作用，这一假设仍有待检验。基于这些观察结果，我们推荐在药理学或毒理学暴露及F%研究中采用尾端采血技术，特别是在早期发现工作中。眶后出血存在争议，不再被视为一种人道方法。插管采血，尤其是与自动血液采集技术相结合，已成为制药行业进行大鼠生物利用度研究的最有效方法。
