Abstract

Expression of the organic anion transporting polypeptide 1B1 (OATP1B1) is regulated by transcription factor hepatic nuclear factor (HNF) 1α. The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA), an inhibitor of transcription factor HNF1α, 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 HNF1α. They highlight a novel mechanism of OATP1B1-based interaction that is mediated by transcription factor HNF1α.