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pH-Dependent Bidirectional Transport of Weakly Basic Drugs Across Caco-2 Monolayers: Implications for Drug–Drug Interactions

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Abstract

Purpose. The purpose of this study was to investigate the pH-dependent passive and active transport of weakly basic drugs across the human intestinal epithelium.

Methods. The bidirectional pH-dependent transport of weak bases was studied in Caco-2 cell monolayers in the physiologic pH range of the gastrointestinal tract.

Results. 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.

Conclusions. 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.

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Authors and Affiliations

  1. DMPK & Bioanalytical Chemistry, AstraZeneca, SE-431 83, Mölndal, Sweden

    Sibylle Neuhoff & Anna-Lena Ungell

  2. Department of Pharmacy, Division of Pharmaceutics, Uppsala University, Box 580, SE-751 23, Uppsala, Sweden

    Sibylle Neuhoff & Per Artursson

  3. Lead Molecular Design, S.L., ES-08190, Barcelona, Spain

    Ismael Zamora

  4. Grupo de Recerca en Informática Biomédica, Universitat Pompeu Fabra, ES-08003, Barcelona, Spain

    Ismael Zamora

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  1. Sibylle Neuhoff
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Correspondence to Per Artursson.

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Neuhoff, S., Ungell, AL., Zamora, I. et al. pH-Dependent Bidirectional Transport of Weakly Basic Drugs Across Caco-2 Monolayers: Implications for Drug–Drug Interactions. Pharm Res 20, 1141–1148 (2003). https://doi.org/10.1023/A:1025032511040

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