Effects of ursodeoxycholic acid on P-glycoprotein and cytochrome P450 3A4-dependent pharmacokinetics in humans

Background and Objective: On the basis of in vitro studies indicating that ursodeoxycholic acid (UDCA) is a cytochrome P450 (CYP) 3A4 inducer and a pregnane X receptor activator and because the pregnane X receptor is a transcriptional regulator of multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp), we postulated that UDCA might decrease the bioavailability of CYP3A4 and P-gp probe drugs in humans. The main objective of this Study was to determine whether UDCA alters the pharmacokinetics of digoxin and midazolam. The secondary objective was to determine whether the intestinal expression of P-gp and CYP3A4 is increased by UDCA. Methods: The effect of UDCA oil MDR1 and CYP3A4 messenger ribonucleic acid (mRNA) expression was investigated in human colon carcinoma cell lines LS174T and Caco-2. Eight healthy volunteers participated in this open, nonrandomized 2-period study, in which the effects of UDCA (13 mg (.) kg(-1) (.) d(-1) during 2 weeks) versus control on the pharmacokinetics of digoxin (0.5-mg single intravenous infusion), d(3)-digoxin (3-fold deuterated digoxin, 0.5-mg single oral dose), and midazolam (7.5-mg single oral dose) were compared. Duodenal biopsy specimens were obtained during both periods to quantify, MDR1/P-gp and CYP3A4 expression. Results: In vitro UDCA induced MDR1 and CYT3A4 mRNA in Caco-2 cells but not in LS174T cells. In humans UDCA significantly decreased the extent of digoxin absorption from 0.77 to 0.70 and the oral d(3)-digoxin area under the plasma concentration-time curve from 0 to 4 hours from 6.4 +/- 1.7 ng (.) h (.) mL(-1) to 5.3 +/- 1.5 ng (.) h (.) mL(-1) (P = .01 and P = .05, respectively). UDCA had no detectable effects oil the pharmacokinetics of miclazolam or the intestinal mRNA and protein expression levels of MDRI/P-gp and CYP3A4. Conclusion: Under the conditions in our study, UDCA only modestly decreased digoxin disposition without detectable changes in midazolam pharmacokinetics. The clinical relevance of these findings remains to be determined.