Hanafy A, Langguth P, Spahn-Langguth H
Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle/Saale, Germany.
Eur J Pharm Sci. 2001 Feb;12(4):405-15. doi: 10.1016/s0928-0987(00)00195-0.
The expression of P-glycoprotein is induced in cell cultures upon exposure to various inducers. Therefore, the aim of the present study was to evaluate the in-vivo relevance of this observation, i.e. the influence of chronic pretreatments with selected drugs -- all of which are ligands to P-glycoprotein (P-gp) as demonstrated in radioligand binding studies and all of which have some or a considerable effect on P-gp expression in Caco-2 cells -- on the effective intestinal permeabilities of the model compound talinolol in rats employing in-situ single-pass intestinal perfusion of three different gut segments. Talinolol was selected, because it shows high selectivity for one of the exsorptive transporters (P-gp) and its intestinal permeability is very sensitive to changes in exsorption when the perfusate concentration is low. Prior to the induction study the perfusion model was optimized regarding the type and concentration of a competitive inhibitor which may be used to block the exsorption-related permeability reduction (through intestinal exsorption) during an ongoing perfusion and would permit an intra-individual comparison of the effective permeability without and with blockade of exsorption. While repetitive verapamil and talinolol dosing had no statistically significant exsorption-inducing effect, vinblastine and rifampicin pretreatments resulted in decreased intestinal talinolol permeabilities in the three tested gut segments, duodenum, jejunum, and colon [e.g., S-talinolol in jejunum: control, 2.50 x 10(-4) cm/s; vinblastine induction, 1.48 x 10(-4) cm/s (P<0.05); rifampicin induction, 1.51 x 10(-4) cm/s (P<0.05)]. Addition of an efficient secretion inhibitor (vinblastine) to the perfusate permitted the determination of the impact of inhibitable secretory processes on the total effective permeabilities and an estimation of passive permeability in the respective individual. The inhibitable permeability fractions were higher for vinblastine than for any other pretreatment and the difference from control pretreatment was statistically significant for all intestinal segments (duodenum, 61.8%; jejunum, 63.1%; colon, 43,7%; S-talinolol). Statistically significant differences were also detected for rifampicin in the perfused duodenum and jejunum (33.1 and 27.5% increase in inhibitable fraction, respectively, for S-talinolol). These differences are explained by a significant induction of outside-directed transport in the intestinal enterocytes by vinblastine and rifampicin.
在细胞培养中，当暴露于各种诱导剂时，P-糖蛋白的表达会被诱导。因此，本研究的目的是评估这一观察结果在体内的相关性，即使用三种不同肠段的原位单通道肠灌注法，研究选定药物（在放射性配体结合研究中均为P-糖蛋白（P-gp）的配体，且在Caco-2细胞中对P-gp表达均有一定或显著影响）的慢性预处理对大鼠模型化合物他林洛尔有效肠通透性的影响。选择他林洛尔是因为它对其中一种吸收性转运体（P-gp）具有高选择性，并且当灌注液浓度较低时，其肠通透性对吸收变化非常敏感。在诱导研究之前，对灌注模型进行了优化，涉及竞争性抑制剂的类型和浓度，该抑制剂可用于在持续灌注过程中阻断与吸收相关的通透性降低（通过肠道吸收），并允许在个体内比较有无吸收阻断时的有效通透性。虽然重复给予维拉帕米和他林洛尔没有统计学上显著的吸收诱导作用，但长春碱和利福平预处理导致在三个测试肠段（十二指肠、空肠和结肠）中肠他林洛尔通透性降低[例如，空肠中S-他林洛尔：对照组，2.50×10⁻⁴ cm/s；长春碱诱导组，1.48×10⁻⁴ cm/s（P<0.05）；利福平诱导组，1.51×10⁻⁴ cm/s（P<0.05）]。向灌注液中添加高效分泌抑制剂（长春碱）可以确定可抑制分泌过程对总有效通透性的影响，并估计各个体中的被动通透性。长春碱的可抑制通透性分数高于任何其他预处理，并且与对照预处理的差异在所有肠段（十二指肠，61.8%；空肠，63.1%；结肠，43.7%；S-他林洛尔）中均具有统计学显著性。在灌注的十二指肠和空肠中，利福平也检测到统计学上显著的差异（S-他林洛尔的可抑制分数分别增加33.1%和27.5%）。这些差异是由于长春碱和利福平显著诱导了肠上皮细胞外向转运所致。
