Neuhoff Sibylle, Ungell Anna-Lena, Zamora Ismael, Artursson Per
AstraZeneca, DMPK & Bioanalytical Chemistry, SE-431 83 Mölndal, Sweden.
Pharm Res. 2003 Aug;20(8):1141-8. doi: 10.1023/a:1025032511040.
The purpose of this study was to investigate the pH-dependent passive and active transport of weakly basic drugs across the human intestinal epithelium.
The bidirectional pH-dependent transport of weak bases was studied in Caco-2 cell monolayers in the physiologic pH range of the gastrointestinal tract.
A net secretion of atenolol and metoprolol was observed when a pH gradient was applied. However, the bidirectional transport of both compounds was equal in the nongradient system. Hence, at lower apical than basolateral pH a change in passive transport caused by an imbalance in the concentration of the uncharged drug species resulted in a "false" asymmetry (efflux ratio). Furthermore, a mixture of pH-dependent passive and active efflux was found for the P-glycoprotein (P-gp, MDR1, ABCB1) substrates, talinolol and quinidine, but not for the neutral drug, digoxin. However, the clinically important digoxin-quinidine interaction depended on the presence of a pH gradient. Hence, the degree of interaction depends on the amount of quinidine available at the binding site of the P-gp.
Active efflux of weak bases can only be accounted for when the fraction of unionized drug species is equal in all compartments because the transport is biased by a pH-dependent passive component. However, this component may take part in vivo and contribute to drug-drug interactions involving P-gp.
本研究旨在调查弱碱性药物在人肠上皮细胞中的pH依赖性被动转运和主动转运。
在胃肠道生理pH范围内，在Caco-2细胞单层中研究了弱碱的双向pH依赖性转运。
当施加pH梯度时，观察到阿替洛尔和美托洛尔的净分泌。然而，在非梯度系统中，这两种化合物的双向转运是相等的。因此，当顶端pH低于基底外侧pH时，由不带电荷药物种类浓度不平衡引起的被动转运变化导致“假”不对称（流出比率）。此外，发现P-糖蛋白（P-gp，MDR1，ABCB1）底物他林洛尔和奎尼丁存在pH依赖性被动转运和主动流出的混合情况，但中性药物地高辛不存在这种情况。然而，临床上重要的地高辛-奎尼丁相互作用取决于pH梯度的存在。因此，相互作用的程度取决于P-gp结合位点处可用奎尼丁的量。
只有当所有隔室中未电离药物种类的比例相等时，弱碱的主动流出才能得到解释，因为转运受到pH依赖性被动成分的影响。然而，该成分可能在体内起作用，并导致涉及P-gp的药物相互作用。
