Received for publication January 17, 2008.
Revised April 22, 2008.
Accepted for publication April 23, 2008.

HNF1 INHIBITOR URSODEOXYCHOLIC ACID (UDCA) INFLUENCES PHARMACOKINETICS OF the OATP1B1 SUBSTRATE ROSUVASTATIN AND BILIRUBIN

Abstract

Expression of the organic anion transporting polypeptide 1B1 (OATP1B1) is regulated by transcription factor HNF1. 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 oral dose of 20mg rosuvastatin after 14 days of oral intake of either 500mg UDCA or placebo. Plasma concentrations of rosuvastatin were determined on day 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 AUC_0-72 from 128.5ng/mL*h to 182.1ng/mL*h (P=0.008) compared with the control group. The oral clearance decreased from 155.2L/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 which is mediated by transcription factor HNF1.

Key words: drug interactions, human pharmacokinetics, inhibition, organic anion transport