The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin

Abstract

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...

Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

“…Considering that erlotinib is metabolized primarily by the CYP3A4 enzyme system (22) and that rifampicin and ketoconazole are wellknown CYP3A4 inducer and inhibitor, respectively, these drug-drug interactions have been considered as primarily CYP3A4 mediated. However, given that rifampicin has been shown to induce also intestinal P-gp (23,24) and that ketoconazole is a P-gp inhibitor (25,26), although the effects of these two drugs on CYP3A expression/activity are expected to be greater and therefore more clinically relevant compared with the modulation of P-gp, a potential contribution of ATP-binding cassette drug efflux transporters to these interactions cannot completely be excluded.…”

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

“…It is suggested that P-glycoprotein (P-gp) and/or CYP3A limit the oral bioavailability of digoxin, rifampin [4], vinblastine [5], dexamethasone tromethorphan [6], tacrolimus [7], sirolimus [8] and cyclosporin A [9,10]. Lown et al [11] suggested that P-glycoprotein…”

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

“…Although CYP3A in duodenal samples was enhanced 4.4-fold, there was no correlation between the AUC of digoxin and CYP3A4 expression of individual volunteers. 92 These data strongly indicate that P-gp modulates intestinal digoxin absorption, leading to low drug concentrations in individuals with high P-gp expression and high concentrations in those with low P-gp expression. 92 Accordingly, rifampin-mediated P-gp induction is associated with a reduction of plasma digoxin.…”

“…90,91 It was recently reported that concomitant administration of rifampin at a dose of 600 mg/day for 10 days in healthy volunteers reduced digoxin plasma concentrations substantially after an oral single-dose (1 mg) administration compared with the plasma-time profile without rifampin treatment. 92 The effect was less pronounced after intravenous administration of digoxin.…”