title: Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1.
abstract: Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genome-wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10-8). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q-value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Giacomini
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Hsueh
authors.affiliation: Research and Development Drug Disposition, Sanofi-Aventis Deutschland, Frankfurt, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Weitz
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Metabolon, Inc., Durham, North Carolina, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Kinchen
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: A
authors.initials: A
authors.lastname: Coelho
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Zur
authors.affiliation: Research and Development Drug Disposition, Sanofi-Aventis Deutschland, Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Mertsch
authors.affiliation: Disposition Safety and Animal Research, Sanofi-Aventis, Great Valley, Pennsylvania, USA.
authors.forename: W
authors.initials: W
authors.lastname: Brian
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Kroetz
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA. kathy.giacomini@ucsf.edu.|Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA. kathy.giacomini@ucsf.edu.
authors.forename: K M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D001647:Bile Acids and Salts / Q000097:blood*; D015415:Biomarkers / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000097:blood*; D004347:Drug Interactions / Q000235:genetics; D005227:Fatty Acids / Q000097:blood*; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D055432:Metabolomics; D009226:Myristates / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D003998:Dicarboxylic Acids; D005227:Fatty Acids; D027381:Liver-Specific Organic Anion Transporter 1; D009226:Myristates; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D010169:Palmitic Acids; C503999:SLCO1B1 protein, human; C114338:organic anion transport protein 3; C012346:hexadecanedioic acid; D016572:Cyclosporine; D017035:Pravastatin