目的:能够同时测量体内多个部位的特定分子,时间分辨率为秒,可以大大促进我们对药物运输和消除的理解。
方法:作为原理证明,在这里,我们描述了使用基于电化学适体(EAB)的传感器来测量抗生素万古霉素从活体大鼠血浆(在颈静脉中测量)到脑脊液(在侧脑室中测量)的转运,时间分辨率为几秒钟.
结果:在我们的第一次努力中,我们只在脑室做了测量.这样做,我们发现,尽管在单一药物生命周期内收集数百个浓度值可以对描述颅内运输的参数进行高精度估计,由于数学上的等价,这些数据对该药物的血浆药代动力学产生了两种不同的描述,它们同样很好地符合脑内观察。同时收集静脉测量,然而,解决了这种歧义,能够对描述个体动物从血液到脑脊液转运的关键药代动力学参数进行高精度估计(在95%置信水平下通常为±5~±20%).
结论:同时,高密度\'在静脉\'(血浆)和\'在脑\'(脑脊液)测量提供了独特的机会来探索几乎普遍用于早期的隔室模型的药物运输,允许定量评估,例如,生理过程的药代动力学作用,例如药物通过硬脑膜静脉窦从CNS中大量运输。
OBJECTIVE: The ability to measure specific molecules at multiple sites within the body simultaneously, and with a time resolution of seconds, could greatly advance our understanding of drug transport and elimination.
METHODS: As a proof-of-principle demonstration, here we describe the use of electrochemical aptamer-based (EAB) sensors to measure transport of the antibiotic vancomycin from the plasma (measured in the jugular vein) to the cerebrospinal fluid (measured in the lateral ventricle) of live rats with temporal resolution of a few seconds.
RESULTS: In our first efforts, we made measurements solely in the ventricle. Doing so we find that, although the collection of hundreds of concentration values over a single drug lifetime enables high-precision estimates of the parameters describing intracranial transport, due to a mathematical equivalence, the data produce two divergent descriptions of the drug\'s plasma pharmacokinetics that fit the in-brain observations equally well. The simultaneous collection of intravenous measurements, however, resolves this ambiguity, enabling high-precision (typically of ±5 to ±20% at 95% confidence levels) estimates of the key pharmacokinetic parameters describing transport from the blood to the cerebrospinal fluid in individual animals.
CONCLUSIONS: The availability of simultaneous, high-density \'in-vein\' (plasma) and \'in-brain\' (cerebrospinal fluid) measurements provides unique opportunities to explore the assumptions almost universally employed in earlier compartmental models of drug transport, allowing the quantitative assessment of, for example, the pharmacokinetic effects of physiological processes such as the bulk transport of the drug out of the CNS via the dural venous sinuses.