Investigation of Glycochenodeoxycholate Sulfate and Chenodeoxycholate Glucuronide as Surrogate Endogenous Probes for Drug Interaction Studies of OATP1B1 and OATP1B3 in Healthy Japanese Volunteers
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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.
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).
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.
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.
KEY WORDSbile acids drug–drug interaction endogenous substrates hepatobiliary transport organic anion transporting polypeptide (OATP)
Area under the plasma concentration–time curve
Breast cancer resistance protein
Bile salt export pump
Farnesoid X receptor
Human embryonic kidney 293
Liquid chromatography–tandem mass spectrometry
Lower limit of quantification
Lower limit of quantitation
Multiple reaction monitoring
Multidrug resistance-associated protein
Sodium-taurocholate cotransporting polypeptide
Organic anion transporter
Organic anion transporting polypeptide 1B1
Organic anion transporting polypeptide 1B3
Organic anion transporting polypeptide 2B1
Positron emission tomography
Small heterodimer partner.
Acknowledgments and Disclosures
This study was financially supported partly by a Grant-in-Aid for Scientific Research (S) [Grant 24,229,002], partly by the Research on Development of New Drugs from the Japan Agency for Medical Research and Development, and partly by a Grant-in-Aid from the Japan Research Foundation for Clinical Pharmacology.
Wrote Manuscript: Issey Takehara, Nobuaki Watanabe, Kazuya Maeda, Osamu Ando, Yuichi Sugiyama, and Hiroyuki Kusuhara
Designed Research: Issey Takehara, Takashi Yoshikado, Miwa Yoshida, Kenichi Furihata, Nobuaki Watanabe, Kazuya Maeda, Osamu Ando, Yuichi Sugiyama, and Hiroyuki Kusuhara
Performed Research: Issey Takehara, Hanano Terashima, Takeshi Nakayama, Kazuya Maeda
Analyzed Data: Takehara, Hanano Terashima, Nobuaki Watanabe, Kazuya Maeda, Yuichi Sugiyama, and Hiroyuki Kusuhara
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