To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology ( n = 21) or by plasma concentrations after orally administered digoxin ( n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population ( n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

Marked interindividual variability in plasma concentrations of drugs after administration of a fixed dose is often related to differences in drug metabolism. Inhibition and induction of hepatic drug metabolism, and also of prehepatic biotransformation in the intestine, are important and well-established mechanisms for drug interactions. A number of clinical important drug interactions with rifampicin have been reported that are caused by its powerful induction of intestinal cytochrome P4503A4 (1, 2). We have observed a 53-year-old patient taking chronic digoxin in whom concentrations of digoxin decreased below detectable limits when he was treated for bacterial endocarditis with rifampin. A literature search identified 2 further case reports of digoxin-rifampin interactions (3, 4), both describing a 50% reduced concentration of digoxin. Induction of digoxin's metabolism as a mechanism underlying this interaction is rather unlikely, because digoxin is eliminated from the body by renal and biliary excretion of unchanged drug and its metabolism is negligible (5, 6). The data could be reconciled with the clinical observation if rifampin, in addition to its effect on drug metabolism, induces expression of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp), the mdr-1 gene product, in the intestine.Indeed, digoxin has been identified in in vitro and animal experiments as a substrate of renal (7, 8) and intestinal P-gp (9, 10). A potential role for P-gp in the intestinal absorption and prehepatic elimination of numerous drugs (e.g., digoxin) has been recognized (11). These experiments suggest a major role for P-gp in the interaction of digoxin with other drugs, such as quinidine (12, 13). After administration of digoxin to mdr1a -/-mice, concentrations of digoxin in brain and plasma were 35-and 2-fold higher, respectively, compared with wild-type (10). Other data from P-gp knockout mice indicate a considerable reduction of direct intestinal secretion of digoxin into the gut lumen in knockout mice but no significant decrease in biliary and renal excretion of digoxin (14). Both its location at the apical membrane of enterocytes and its function as an efflux pump suggest a particular role of intestinal P-gp for the disposition of digoxin. Inhibition of intestinal P-gp by oral treatment with the P-gp inhibitor PSC833 (18) increases bioavailability of concomitantly administered drugs. In contrast to such inhibition, recent experimental evidence obtained from human colon carcinoma cell lines indicates that P-gp expression is upregulated by rifampin (19). If rifampin induces intestinal P-gp in humans, and digoxin is transported from apical duodenal cells during absorption back into the lumen of the intestine, then coadministration of Recent data point to the contribution of P-glycoprotein (P-gp) to digoxin elimination. On the basis of clinical observations of patients in whom digoxin levels decreased considerably when treated with rifampin, we hypothesized that concomitant rifampin therapy may affect digoxin disp...

This work demonstrated a much higher content of both CYP3A4 protein and P-glycoprotein in enterocytes isolated from human duodenal or jejunal mucosa than in paired specimens of liver tissue. These results lend support to the view that biotransformation in the gut wall substantially contributes to the overall first-pass metabolism of many CYP3A4 substrates. Furthermore, the high content of P-glycoprotein on the apical surface of enterocytes supports the theory that this efflux transporter may act in concert with CYP3A4 to limit oral drug bioavailability. Finally, these results indicate that neither CYP3A4 nor MDR1 (P-glycoprotein) is coordinately regulated in the liver and intestine.