Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1
| Autor: | William Brian, Xiaomin Liang, Kathleen M. Giacomini, Dietmar Weitz, Jason M. Kinchen, Katharina Mertsch, Marilyn M. Giacomini, Deanna L. Kroetz, Srijib Goswami, Arik A. Zur, Sook Wah Yee, Annabelle Coelho, Chia Hsiang Hsueh |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Organic anion transporter 1 Metabolite Organic Anion Transporters Genome-wide association study Palmitic Acids Pharmacology Organic Anion Transporters Sodium-Independent 030226 pharmacology & pharmacy Article Bile Acids and Salts 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Metabolomics Organic Anion Transport Protein 1 In vivo Metabolome Genetics Humans Pharmacology (medical) Dicarboxylic Acids Drug Interactions Pharmacology & Pharmacy Pravastatin Sodium-Independent chemistry.chemical_classification biology Myristates Liver-Specific Organic Anion Transporter 1 Fatty Acids Human Genome Fatty acid Transporter Pharmacology and Pharmaceutical Sciences 030104 developmental biology HEK293 Cells chemistry Biochemistry biology.protein Cyclosporine Biomarkers Genome-Wide Association Study |
| Zdroj: | Clinical pharmacology and therapeutics, vol 100, iss 5 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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