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pH-Dependent passive and active transport of acidic drugs across Caco-2 cell monolayers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2005 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 2-3, 211-220 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate pH-dependent passive and active transport of acidic drugs across Caco-2 cells. Therefore, the bidirectional pH-dependent transport of two acidic drugs, indomethacin and salicylic acid, across Caco-2 cells was studied in the physiological pH range of the gastrointestinal tract. The transport of both drugs decreased with increased pH, as expected from the pH-partition hypothesis. Net absorption occurred when the basolateral pH exceeded the apical pH. Concentration dependence and transporter inhibition studies indicated passive transport for indomethacin and a mixture of pH-dependent passive and active influx for salicylic acid. Unexpectedly, active and passive drug transport results were indistinguishable in temperature dependency studies. The transport of salicylic acid (apical pH 5.0; basolateral pH 7.4) was partly blocked by inhibitors of the proton-dependent transporters MCT1 (SLC16A1) and OATP-B (SLC21A9, SLCO2B1). This study shows that the asymmetry in bidirectional transport of acidic drugs is affected by both passive and active components in the presence of pH gradients across Caco-2 cells. Thus, combined studies of concentration-dependency and transport-inhibition are preferred when acidic drug transport is studied in a pH gradient. The findings of this in vitro study can be extrapolated to in vivo situations involving an acidic microclimate.

Place, publisher, year, edition, pages
2005. Vol. 25, no 2-3, 211-220 p.
Keyword [en]
Biological Transport; Active, Caco-2 Cells, Cell Membrane/*metabolism, Cell Membrane Permeability/*drug effects, Humans, Hydrogen-Ion Concentration, Indomethacin/*pharmacokinetics, Research Support; Non-U.S. Gov't, Salicylic Acid/*pharmacokinetics
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93110DOI: 10.1016/j.ejps.2005.02.009PubMedID: 15911216OAI: oai:DiVA.org:uu-93110DiVA: diva2:166488
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Refined in vitro Models for Prediction of Intestinal Drug Transport: Role of pH and Extracellular Additives in the Caco-2 Cell Model
Open this publication in new window or tab >>Refined in vitro Models for Prediction of Intestinal Drug Transport: Role of pH and Extracellular Additives in the Caco-2 Cell Model
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug transport across the intestinal epithelium is roughly predicted from permeability values obtained from Caco-2 cell monolayers. This thesis examines the important role of pH and extracellular additives for increasing the reliability and predictivity of the in vitro screening system, Caco-2.

It was shown that the passive transport of ionizable compounds may be biased by a false efflux or uptake component, when applying a physiological pH-gradient across the membrane. pH also affected the amount of compound available at the transporter-binding site. Therefore, pH dependence should be considered in studies of such compounds and of drug-drug interactions involving efflux transporters. It was also shown that proton-dependent apical uptake or basolateral efflux should be studied both with and without a pH gradient over the whole monolayers.

The two extracellular additives, bovine serum albumin (BSA) and the solubilizing agent, Cremophor® EL, also influenced Caco-2 permeabilities. BSA applied to the receiver side increases, and to the donor side decreases drug permeation according to the drug’s protein binding capacity. Thus, the absorptive transport for both passive and active compounds is favoured, giving a physiologically sound improvement of the Caco-2 cell model. Inclusion of BSA increased both the predictivity and quality of permeability studies, particularly of highly lipophilic, BCS class II compounds. Passive and active transport processes could also be distinguished after accounting for unbound concentrations. The overall effect of Cremophor® EL on the permeability to a drug was compound-specific and probably dependent on micellar incorporation. Cremophor® EL can therefore not be recommended.

Neither pH nor BSA affect the functionality of transporters such as P-glycoprotein. However, efflux ratios of ionizable or protein bound drugs are altered in the presence of a pH-gradient or BSA, indicating that an experimental system without protein or pH gradient can over- or underestimate active and passive efflux in drug transport.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 14
Keyword
Pharmacy, Caco-2 cells, membrane permeability, drug permeation, drug efflux ratios, drug uptake ratios, Cremophor EL, bovine serum albumin, pH-dependent permeability, drug transport, FARMACI
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-5814 (URN)91-554-6262-6 (ISBN)
Public defence
2005-06-02, B22, Uppsala Biomediciniska centrum, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2011-09-19Bibliographically approved

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