The effect of rifampin treatment on intestinal expression of human MRP transporters

Abstract

The importance of the ATP-dependent transporter P-glycoprotein, which is expressed in the brush border membrane of enterocytes and in other tissues with excretory function, for overall drug disposition is well recognized. For example, induction of intestinal P-glycoprotein by rifampin appears to be the underlying mechanism of decreased plasma concentrations of P-glycoprotein substrates such as digoxin with concomitant rifampin therapy. The contribution of transporter proteins other than P-glycoprotein to drug interactions in humans has not been elucidated. Therefore, we tested in this study the hypothesis whether the conjugate export pump MRP2 (cMOAT), which is another member of the ABC transporter family, is inducible by rifampin in humans. Duodenal biopsies were obtained from 16 healthy subjects before and after nine days of oral treatment with 600 mg rifampin/day. MRP2 mRNA and protein were determined by reverse transcription-polymerase chain reaction and immunohistochemistry. Rifampin induced duodenal MRP2 mRNA in 14 out of 16 individuals. Moreover, MRP2 protein, which was expressed in the apical membrane of enterocytes, was significantly induced by rifampin in 10 out of 16 subjects. In summary, rifampin induces MRP2 mRNA and protein in human duodenum. Increased elimination of MRP2 substrates (eg, drug conjugates) into the lumen of the gastrointestinal tract during treatment with rifampin could be a new mechanism of drug interactions.

Figure 1.

mRNA expression of MRP1 and villin in duodenal biopsies of 8 healthy volunteers before and after 9 days of treatment with 600 mg/day rifampin.

Figure 2.

mRNA expression of MRP2 and villin in duodenal biopsies of 16 healthy volunteers before and after 9 days of treatment with 600 mg/day rifampin.

Figure 3.

Individual data and mean values (±SD) of MRP2 mRNA expression normalized for villin mRNA in duodenal biopsies of 16 healthy volunteers before and after 9 days of treatment with 600 mg/day rifampin (*** P < 0.001).

Figure 4.

Duodenal biopsies (villus tip, ×40, hemalaun) of one healthy volunteer (subject 15) before (A) and after 9 days of treatment with 600 mg/day rifampin (B) immunostained for MRP2.

Figure 5.

Individual data and mean values (±SD) of MRP2 protein expression in duodenal biopsies of 16 healthy volunteers before and after 9 days of treatment with 600 mg/day rifampin (* P < 0.05).