QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.108.020503v1 36/8/1453    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by He, Y.-J. Articles by Zhou, H.-H. PubMed PubMed Citation Articles by He, Y.-J. Articles by Zhou, H.-H.

SHORT COMMUNICATION

Hepatic Nuclear Factor 1 Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin

Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China (Y.-J.H., W.Z., J.-H.T., Y.C., D.G., Q.L., Z.-Y.L., H.C., D.-L.H., D.W., H.-H.Z.); and Institute of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany (Y.-J.H., J.K.)

Expression of the organic anion transporting polypeptide 1B1 (OATP1B1) is regulated by transcription factor hepatic nuclear factor (HNF) 1. The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA), an inhibitor of transcription factor HNF1, on rosuvastatin and bilirubin kinetics in human healthy volunteers. Both substances are substrates of OATP1B1. Twelve subjects with OATP1B1^*1b/^*1b genotype predicting high transport activity were recruited for this randomized, crossover study. Each subject received a single p.o. dose of 20 mg of rosuvastatin after 14 days of p.o. intake of either 500 mg of UDCA or placebo. Plasma concentrations of rosuvastatin were determined on days 15 to 18 of each study period. Subjects were randomly assigned to UDCA or placebo group. Intake of UDCA led to a significant increase in rosuvastatin area under the curve (AUC)_0–72 from 128.5 ng/ml · h to 182.1 ng/ml · h(P = 0.008) compared with the control group. The oral clearance decreased from 155.2 l/h with placebo to 109.8 l/h with UDCA. In addition, the mean values of total bilirubin, conjugated bilirubin, and unconjugated bilirubin significantly increased to 139 ± 39% (P = 0.003), 127 ± 29% (P = 0.005), and 151 ± 52% (P = 0.004), respectively, after UDCA treatment. These results in healthy volunteers confirm the findings from in vitro studies that UDCA inhibits OATP1B1 activity by inhibition of the transcription factor HNF1. They highlight a novel mechanism of OATP1B1-based interaction that is mediated by transcription factor HNF1.