Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Drug Metab Dispos. 2012 Sep;40(9):1846-53. doi: 10.1124/dmd.112.045500. Epub 2012 Jun 19.
A widely used metric of substrate exposure in brain is the brain-to-serum partition coefficient (K(p,brain); C(brain)/C(serum)), most appropriately determined at distribution equilibrium between brain tissue and serum. In some cases, C(brain)/C(serum) can peak and then decrease, as opposed to monotonically increasing to a plateau, precluding accurate estimation of partitioning. This "overshoot" has been observed with compounds that undergo enterohepatic recycling (ER), such as valproic acid (VPA). Previous simulation experiments identified a relationship between overshoot in the C(brain)/C(serum) versus time profile and distribution into a peripheral "compartment" (e.g., the ER loop). This study was conducted to evaluate model predictions of that relationship. Initial experiments tested the ability of activated charcoal, antibiotics, or Mrp2 deficiency to impair VPA ER in rats, thereby limiting the apparent volume of distribution associated with ER. Mrp2 deficiency (significantly) and antibiotics (moderately) interrupted VPA ER. Subsequently, brain partitioning was evaluated in the presence versus absence of ER modulation. Although overshoot was not eliminated completely, deconvolution revealed that overshoot was reduced in Mrp2-deficient and antibiotic-treated rats. Consistent with model predictions, overshoot was higher after antibiotic treatment (moderate ER interruption) than in Mrp2 deficiency (substantial ER interruption). Steady-state K(p,brain) was unaffected by experimental manipulation, also consistent with model predictions. These data support the hypothesis that C(brain)/C(serum) may overshoot K(p,brain) based on the extent of peripheral sequestration. Consideration of this information, particularly for compounds that undergo significant extravascular distribution, may be necessary to avoid erroneous estimation of K(p,brain).
脑内物质暴露的常用度量标准是脑-血清分配系数（K(p,brain); C(brain)/C(serum)），最合适的测定方法是在脑组织和血清之间达到分布平衡时进行。在某些情况下，C(brain)/C(serum)可能会先升高然后降低，而不是单调地升高到一个平台，从而无法准确估计分配。这种“超调”在经历肠肝循环（ER）的化合物中已经观察到，如丙戊酸（VPA）。先前的模拟实验确定了 C(brain)/C(serum)与时间曲线的超调与分布到外周“隔室”（例如 ER 循环）之间的关系。这项研究旨在评估该关系的模型预测。最初的实验测试了活性炭、抗生素或 Mrp2 缺乏对大鼠 VPA ER 的影响，从而限制了与 ER 相关的表观分布体积。Mrp2 缺乏（显著）和抗生素（中度）中断了 VPA ER。随后，在存在和不存在 ER 调节的情况下评估了脑内分配。尽管超调没有完全消除，但反卷积显示，Mrp2 缺乏和抗生素治疗的大鼠中，超调幅度降低。与模型预测一致，抗生素治疗（中度 ER 中断）后的超调幅度高于 Mrp2 缺乏（大量 ER 中断）。稳态 K(p,brain)不受实验操作的影响，这也与模型预测一致。这些数据支持了这样一种假设，即 C(brain)/C(serum)可能会根据外周隔离的程度超过 K(p,brain)。对于经历大量血管外分布的化合物，考虑到这一信息可能是避免错误估计 K(p,brain)所必需的。
