pH-Dependent passive and active transport of acidic drugs across Caco-2 cell monolayers.
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.
Neuhoff
Sibylle
S
Department of Pharmacy, Division of Pharmaceutics, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden. sibylle.neuhoff@farmaci.uu.se
Ungell
Anna-Lena
AL
Zamora
Ismael
I
Artursson
Per
P
D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000493:pharmacokinetics*; D020156:Salicylic Acid / Q000493:pharmacokinetics*
D020156:Salicylic Acid; D007213:Indomethacin