Lin T H, Sawada Y, Sugiyama Y, Iga T, Hanano M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Biochem Pharmacol. 1987 Oct 15;36(20):3425-31. doi: 10.1016/0006-2952(87)90321-2.
The effect of uranyl nitrate-induced acute renal failure on the brain uptake of DL-propranolol was investigated in rats with a series of tissue-sampling single-carotid injection techniques. When the buffer solution was used as an injection solution, the brain uptake index (BUI), the extraction ratio (ET), and the blood-brain barrier (BBB) permeability-surface area product (PSapp) and PSu (corrected PSapp for the unbound fraction) in uremic rats were significantly lower than those in control rats. These parameters for DL-propranolol were decreased significantly in both control and uremic rats receiving injection of the uremic serum. The PSu values in both of the control and uremic rats injected with either control or uremic rat serum were significantly higher than those in rats injected with the buffer solution, suggesting the presence of a protein-mediated transport mechanism; that is, the conventional assumption that the fraction of the drug which is available for the uptake in vivo is equal to the unbound fraction as measured in vitro may not hold. In contrast, the brain extraction of D-[14C]glucose, [3H]inulin and [3H]water, which show no binding to serum protein, was not affected by the coinjection of either control or uremic rat serum. On the other hand, using either the ultrafiltrate from serum (control and uremic) or supernatant fraction from heat-treated serum (control and uremic) as the injection solution, no significant difference in the PSu value for DL-propranolol was observed between control and uremic serum. These results suggest that (1) the decrease in the PSu value for DL-propranolol in uremic rats may be attributed mainly to the presence of an endogenous inhibitory substance(s) for the brain uptake or to the decrease in the exchangeable fraction in vivo in the uremic serum; (2) the decrease in the PSu value for DL-propranolol may also be partly attributed to the change in the BBB permeability and/or surface area; (3) the inhibitor for the brain uptake may be characterized as a temperature-sensitive and nonfiltrable substance(s) at physiological pH; and (4) the ability of protein-mediated transport for DL-propranolol into brain was decreased in uremic rats.
采用一系列组织采样单颈动脉注射技术，研究了硝酸铀酰诱导的急性肾衰竭对大鼠脑摄取DL-普萘洛尔的影响。当使用缓冲溶液作为注射溶液时，尿毒症大鼠的脑摄取指数（BUI）、提取率（ET）以及血脑屏障（BBB）通透表面积乘积（PSapp）和PSu（针对未结合部分校正的PSapp）均显著低于对照大鼠。在接受尿毒症血清注射的对照大鼠和尿毒症大鼠中，DL-普萘洛尔的这些参数均显著降低。注射对照或尿毒症大鼠血清的对照大鼠和尿毒症大鼠的PSu值均显著高于注射缓冲溶液的大鼠，这表明存在蛋白质介导的转运机制；也就是说，传统的假设，即体内可用于摄取的药物分数等于体外测定的未结合分数，可能并不成立。相比之下，与血清蛋白无结合的D-[14C]葡萄糖、[3H]菊粉和[3H]水的脑提取不受对照或尿毒症大鼠血清共同注射的影响。另一方面，使用血清（对照和尿毒症）的超滤物或热处理血清（对照和尿毒症）的上清液部分作为注射溶液，对照血清和尿毒症血清之间DL-普萘洛尔的PSu值未观察到显著差异。这些结果表明：（1）尿毒症大鼠中DL-普萘洛尔PSu值的降低可能主要归因于脑摄取的内源性抑制物质的存在或尿毒症血清中体内可交换部分的减少；（2）DL-普萘洛尔PSu值的降低也可能部分归因于血脑屏障通透性和/或表面积的变化；（3）脑摄取抑制剂可能是一种在生理pH下对温度敏感且不可滤过的物质；（4）尿毒症大鼠中蛋白质介导的DL-普萘洛尔向脑内转运的能力降低。
