Investigation of Glycochenodeoxycholate Sulfate and Chenodeoxycholate Glucuronide as Surrogate Endogenous Probes for Drug Interaction Studies of OATP1B1 and OATP1B3 in Healthy Japanese Volunteers

Pharm Res. 2017 Aug;34(8):1601-1614. doi: 10.1007/s11095-017-2184-5. Epub 2017 May 26.


Purpose: To assess the use of glycochenodeoxycholate-3-sulfate (GCDCA-S) and chenodeoxycholate 3- or 24-glucuronide (CDCA-3G or -24G) as surrogate endogenous substrates in the investigation of drug interactions involving OATP1B1 and OATP1B3.

Methods: Uptake of GCDCA-S and CDCA-24G was examined in HEK293 cells transfected with cDNA for OATP1B1, OATP1B3, and NTCP and in cryopreserved human hepatocytes. Plasma concentrations of bile acids and their metabolites (GCDCA-S, CDCA-3G, and CDCA-24G) were determined by LC-MS/MS in eight healthy volunteers with or without administration of rifampicin (600 mg, po).

Results: GCDCA-S and CDCA-24G were substrates for OATP1B1, OATP1B3, and NTCP. The uptake of [3H]atorvastatin, GCDCA-S, and CDCA-24G by human hepatocytes was significantly inhibited by both rifampicin and pioglitazone, whereas that of taurocholate was inhibited only by pioglitazone. Rifampicin elevated plasma concentrations of GCDCA-S more than those of other bile acids. The area under the plasma concentration-time curve for GCDCA-S was 20.3 times higher in rifampicin-treated samples. CDCA-24G could be detected only in plasma from the rifampicin-treatment phase, and CDCA-3G was undetectable in both phases.

Conclusions: We identified GCDCA-S and CDCA-24G as substrates of NTCP, OATP1B1, and OATP1B3. GCDCA-S is a surrogate endogenous probe for the assessment of drug interactions involving hepatic OATP1B1 and OATP1B3.

Keywords: bile acids; drug–drug interaction; endogenous substrates; hepatobiliary transport; organic anion transporting polypeptide (OATP).

MeSH terms

  • Adult
  • Atorvastatin / metabolism
  • Bile Acids and Salts / blood
  • Chenodeoxycholic Acid / metabolism*
  • Drug Interactions
  • Glucuronides / metabolism*
  • Glycochenodeoxycholic Acid / analogs & derivatives*
  • Glycochenodeoxycholic Acid / metabolism
  • HEK293 Cells
  • Hepatocytes / metabolism
  • Humans
  • Liver-Specific Organic Anion Transporter 1 / metabolism*
  • Male
  • Organic Anion Transporters, Sodium-Dependent / metabolism
  • Pioglitazone
  • Rifampin / pharmacology
  • Solute Carrier Organic Anion Transporter Family Member 1B3 / metabolism*
  • Symporters / metabolism
  • Taurocholic Acid / pharmacology
  • Thiazolidinediones / pharmacology
  • Young Adult


  • Bile Acids and Salts
  • Glucuronides
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters, Sodium-Dependent
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Symporters
  • Thiazolidinediones
  • Chenodeoxycholic Acid
  • sodium-bile acid cotransporter
  • Taurocholic Acid
  • Glycochenodeoxycholic Acid
  • glycochenodeoxycholate-3-sulfate
  • Atorvastatin
  • Rifampin
  • Pioglitazone