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Pharmaceutical Research

, Volume 34, Issue 8, pp 1601–1614 | Cite as

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

  • Issey Takehara
  • Hanano Terashima
  • Takeshi Nakayama
  • Takashi Yoshikado
  • Miwa Yoshida
  • Kenichi Furihata
  • Nobuaki Watanabe
  • Kazuya Maeda
  • Osamu Ando
  • Yuichi Sugiyama
  • Hiroyuki KusuharaEmail author
Research Paper

Abstract

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.

KEY WORDS

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

Abbreviations

ABC

ATP-binding cassette

AUC

Area under the plasma concentration–time curve

BCRP

Breast cancer resistance protein

BSEP

Bile salt export pump

C4

7α-hydroxy-4-cholesten-3-one

CDCA

Chenodeoxycholate

CDCA-3G

Chenodeoxycholate-3-glucuronide

CDCA-24G

Chenodeoxycholate-24-glucuronide

CP

Coproporphyrin

DDI

Drug–drug interaction

DHEAS

Dehydroepiandrosterone sulfate

FXR

Farnesoid X receptor

GCA

Glycocholate

GCDCA-S

Glycochenodeoxycholate-3-sulfate

GDCA

Glycodeoxycholate

GLCA

Glycolithocholate

HDA

Hexadecanedionic acid

HEK293

Human embryonic kidney 293

LC–MS/MS

Liquid chromatography–tandem mass spectrometry

LLOQ

Lower limit of quantification

LLOQ

Lower limit of quantitation

MRM

Multiple reaction monitoring

MRP

Multidrug resistance-associated protein

NTCP

Sodium-taurocholate cotransporting polypeptide

OAT

Organic anion transporter

OATP1B1

Organic anion transporting polypeptide 1B1

OATP1B3

Organic anion transporting polypeptide 1B3

OATP2B1

Organic anion transporting polypeptide 2B1

PET

Positron emission tomography

SHP

Small heterodimer partner.

TCA

Taurocholate

TCDCA

Taurochenodeoxycholate

TDA

Tetradecanedionic acid

TDCA

Taurodeoxycholate

TUDCA

Tauroursodeoxycholate

UDCA

Ursodeoxycholate

UGT

UDP-glucuronosyltransferase

Notes

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.

Author Contributions

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

Supplementary material

11095_2017_2184_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1288 kb)

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Issey Takehara
    • 1
    • 2
    • 3
  • Hanano Terashima
    • 2
  • Takeshi Nakayama
    • 2
  • Takashi Yoshikado
    • 4
  • Miwa Yoshida
    • 5
  • Kenichi Furihata
    • 5
  • Nobuaki Watanabe
    • 1
  • Kazuya Maeda
    • 2
  • Osamu Ando
    • 1
  • Yuichi Sugiyama
    • 4
  • Hiroyuki Kusuhara
    • 2
    Email author
  1. 1.Drug Metabolism & Pharmacokinetics Research LaboratoriesDaiichi Sankyo Co., Ltd.TokyoJapan
  2. 2.Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  3. 3.Biomarker DepartmentDaiichi Sankyo Co., Ltd.TokyoJapan
  4. 4.Sugiyama LaboratoryRIKEN Innovation Center, RIKENYokohamaJapan
  5. 5.P-One Clinic, Keikokai Medical CorpTokyoJapan

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