RT Journal Article
SR Electronic
T1 Inhibition of Hepatic Organic Anion-Transporting Polypeptide by RNA Interference in Sandwich-Cultured Human Hepatocytes: An In Vitro Model to Assess Transporter-Mediated Drug-Drug Interactions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1612
OP 1622
DO 10.1124/dmd.110.032995
VO 38
IS 9
A1 Mingxiang Liao
A1 Arek R. Raczynski
A1 Michael Chen
A1 Bei-Ching Chuang
A1 Qing Zhu
A1 Rob Shipman
A1 Jodi Morrison
A1 David Lee
A1 Frank W. Lee
A1 Suresh K. Balani
A1 Cindy Q. Xia
YR 2010
UL http://dmd.aspetjournals.org/content/38/9/1612.abstract
AB Organic anion-transporting polypeptides (OATPs), members of the SLCO/SLC21 family, mediate the transport of various endo- and xenobiotics. In human liver, OATP1B1, 1B3, and 2B1 are located at the basolateral membrane of hepatocytes and are involved in hepatic drug uptake and biliary elimination. Clinically significant drug-drug interactions (DDIs) mediated by hepatic OATPs have drawn great attention from clinical practitioners and researchers. However, there are considerable challenges to prospectively understanding the extent of OATP-mediated DDIs because of the lack of specific OATP inhibitors or substrates and the limitations of in vitro tools. In the present study, a novel RNA interference knockdown sandwich-cultured human hepatocyte model was developed and validated. Quantitative polymerase chain reaction, microarray and immunoblotting analyses, along with uptake assays, illustrated that the expression and transport activity of hepatic OATPs were reduced by small interfering (siRNA) efficiently and specifically in this model. Although OATP siRNA decreased only 20 to 30% of the total uptake of cerivastatin into human hepatocytes, it caused a 50% reduction in cerivastatin metabolism, which was observed by monitoring the formation of the two major metabolites of cerivastatin. The results suggest that coadministration of a drug that is a hepatic OATP inhibitor could significantly alter the pharmacokinetic profile of cerivastatin in clinical studies. Further studies with this novel model demonstrated that OATP and cytochrome P450 have a synergistic effect on cerivastatin-gemfibrozil interactions. The siRNA knockdown sandwich-cultured human hepatocytes may provide a new powerful model for evaluating DDIs.