Inhibition of P-Glycoprotein–Mediated Drug Transport

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Abstract
Background—Although quinidine is known to elevate plasma digoxin concentrations, the mechanism underlying this interaction is not fully understood. Digoxin is not extensively metabolized, but it is known to be transported by the drug efflux pump P-glycoprotein, which is expressed in excretory tissues (kidney, liver, intestine) and at the blood-brain barrier. Accordingly, we tested the hypothesis that inhibition of P-glycoprotein–mediated digoxin transport by quinidine contributes to the digoxin-quinidine interaction. Methods and Results—First, we demonstrated active transcellular transport of both digoxin and quinidine in cultured cell lines that express P-glycoprotein in a polarized fashion. In addition, 5 μmol/L quinidine inhibited P-glycoprotein–mediated digoxin transport by 57%. Second, the effect of quinidine on digoxin disposition was studied in wild-type and in mdr1a(−/−) mice, in which the gene expressing the major digoxin-transporting P-glycoprotein has been disrupted. Because the in vitro data s...

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