Deferme Sven, Mols Raf, Van Driessche Willy, Augustijns Patrick
Laboratory for Pharmacotechnology and Biopharmacy, Herestraat 49, Gasthuisberg, 3000 Leuven, Belgium.
J Pharm Sci. 2002 Dec;91(12):2539-48. doi: 10.1002/jps.10262.
Within the framework of developing strategies to enhance the intestinal absorption of P-glycoprotein (P-gp) substrates, the modulatory effect of a standardized apricot extract on P-gp-related efflux carriers was investigated in the Caco-2 system, Ussing chambers and the rat in situ perfusion model using talinolol as a model substrate. Using the Caco-2 system, polarity in transport of talinolol could be observed, the absorptive transport being much lower than the secretory transport (P(app-abs) = 1.08 +/- 0.29 x 10(-6) cm/s and P(app-secr) = 11.74 +/- 0.80 x 10(-6) cm/s). Inclusion of apricot extract (1%) in the apical medium resulted in a statistically significantly diminished polarity (P(app-abs) = 4.88 +/- 0.96 x 10(-6) cm/s and P(app-secr) = 9.39 +/- 0.58 x 10(-6) cm/s, p < 0.05). In addition, the inhibitory effect of apricot extract on P-gp related efflux mechanisms was shown to be concentration (0% approximately 0.1% < 0.3% < 1%) and pH dependent. Experiments performed with the Ussing chambers resulted in similar observations. In the rat in situ perfusion model, inclusion of apricot extract (1%) in the perfusion medium resulted in a threefold increase of the amount of talinolol appearing in the collected blood compared to the reference condition (23.6 +/- 5.53 pmol/cm. min and 7.13 +/- 1.08 pmol/cm. min, respectively; p < 0.05). Coadministration of this standardized apricot extract might be a safe and useful strategy to enhance the intestinal absorption of P-gp substrates. The nature and structure of the compound(s) responsible for this inhibiting effect on P-gp-related efflux carriers remain to be elucidated, as well as the exact mechanism by which apricot extract exerts its inhibitory function.
在制定提高P-糖蛋白（P-gp）底物肠道吸收策略的框架内，使用他林洛尔作为模型底物，在Caco-2细胞系、尤斯灌流小室和大鼠原位灌注模型中研究了标准化杏提取物对P-gp相关外排载体的调节作用。使用Caco-2细胞系时，可观察到他林洛尔转运的极性，吸收性转运远低于分泌性转运（表观吸收系数P(app-abs) = 1.08 ± 0.29×10⁻⁶ cm/s，表观分泌系数P(app-secr) = 11.74 ± 0.80×10⁻⁶ cm/s）。在顶端培养基中加入杏提取物（1%）导致极性在统计学上显著降低（P(app-abs) = 4.88 ± 0.96×10⁻⁶ cm/s，P(app-secr) = 9.39 ± 0.58×10⁻⁶ cm/s，p < 0.05）。此外，杏提取物对P-gp相关外排机制的抑制作用表现为浓度（0%～0.1% < 0.3% < 1%）和pH依赖性。在尤斯灌流小室中进行的实验得到了类似的结果。在大鼠原位灌注模型中，与对照条件相比，在灌注培养基中加入杏提取物（1%）使收集到的血液中出现的他林洛尔量增加了三倍（分别为23.6 ± 5.53 pmol/cm·min和7.13 ± 1.08 pmol/cm·min；p < 0.05）。联合使用这种标准化杏提取物可能是提高P-gp底物肠道吸收的一种安全有效的策略。导致对P-gp相关外排载体产生这种抑制作用的化合物的性质和结构以及杏提取物发挥其抑制功能的确切机制仍有待阐明。
