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Effects of ursodeoxycholic acid on P‐glycoprotein and cytochrome P450 3A4–dependent pharmacokinetics in humans
Author(s) -
Becquemont Laurent,
Glaeser Hartmut,
Drescher Siegfried,
Hitzl Monika,
Simon Nicolas,
Murdter Thomas E.,
Heinkele Georg,
Hofmann Ute,
Schaefer Christian,
Burk Oliver,
Verstuyft Céline,
Eichelbaum Michel,
Fromm Martin F.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.01.005
Subject(s) - pharmacokinetics , digoxin , ursodeoxycholic acid , cyp3a4 , pharmacology , chemistry , p glycoprotein , organic anion transporting polypeptide , bioavailability , pregnane x receptor , cyp3a , medicine , endocrinology , cytochrome p450 , multiple drug resistance , metabolism , biochemistry , nuclear receptor , transporter , heart failure , transcription factor , gene , antibiotics
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 on 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 CYP3A4 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 on the pharmacokinetics of midazolam or the intestinal mRNA and protein expression levels of MDR1/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. Clinical Pharmacology & Therapeutics (2006) 79 , 449–460; doi: 10.1016/j.clpt.2006.01.005