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Pharmaceutical Research

, Volume 30, Issue 2, pp 447–457 | Cite as

Effect of the Fluoroquinolone Antibacterial Agent DX-619 on the Apparent Formation and Renal Clearances of 6β-Hydroxycortisol, an Endogenous Probe for CYP3A4 Inhibition, in Healthy Subjects

  • Yuichiro Imamura
  • Nobuyuki Murayama
  • Noriko Okudaira
  • Atsushi Kurihara
  • Katsuhisa Inoue
  • Hiroaki Yuasa
  • Takashi Izumi
  • Hiroyuki Kusuhara
  • Yuichi SugiyamaEmail author
Research Paper

Abstract

Purpose

To examine the effect of the fluoroquinolone DX-619 on CYP3A4 and urinary excretion of 6β-hydroxycortisol, an endogenous probe of hepatic CYP3A4 activity, in healthy subjects.

Methods

The effect of DX-619 on CYP3A4 was examined in human liver microsomes. The apparent formation and renal clearance of 6β-hydroxycortisol (CL6β−OHF and CLrenal,6β−OHF, respectively) were determined in placebo- and DX-619-treated subjects. 6β-hydroxycortisol uptake was determined in HEK293 cells expressing OAT1, OAT3, OCT2, MATE1, and MATE2-K.

Results

DX-619 was a mechanism-based inhibitor of CYP3A4, with KI and kinact of 67.9 ± 7.3 μmol/l and 0.0730 ± 0.0033 min−1, respectively. Pharmacokinetic simulation suggested in vivo relevance of CYP3A4 inhibition by DX-619. CL6β−OHF and CLrenal,6β−OHF were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo (P < 0.05). 6β-hydroxycortisol was a substrate of OAT3 (Km = 183 ± 25 μmol/l), OCT2, MATE1, and MATE2-K. Maximum unbound concentration of DX-619 (9.1 ± 0.4 μmol/l) was above Ki of DX-619 for MATE1 (4.32 ± 0.79 μmol/l).

Conclusions

DX-619 caused a moderate inhibition of hepatic CYP3A4-mediated formation and significant inhibition of MATE-mediated efflux of 6β-hydroxycortisol into urine. Caution is needed in applying CL6β−OHF as an index of hepatic CYP3A4 activity without evaluating CLrenal,6β−OHF.

KEY WORDS

CYP3A4 drug-drug interaction mechanism-based inhibition (MBI) renal drug transporter tubular secretion 

Abbreviations

6β-OHF

6β-hydroxycortisol

AUC

area under the concentration-time curve

BBM

brush border membrane

Cmax

maximum plasma concentration

CYP

cytochrome P450

ES

estrone-3-sulfate

HEK

human embryonic kidney

HLM

human liver microsomes

kdeg

degradation rate constant (turnover rate constant) of liver CYP3A4

MRM

multiple reaction monitoring

PAH

para-aminohippuric acid

TEA

tetraethylammonium

Notes

Acknowledgments and Disclosures

The authors acknowledge Ryo Atsumi, for his contribution to the study design and interpretation of results.

Yuichiro Imamura, Nobuyuki Murayama, Noriko Okudaira, Ryo Atsumi, Atsushi Kurihara and Takashi Izumi are employees of Daiichi Sankyo Co., Ltd. Other authors declare no conflict of interest.

The study was sponsored by Daiichi-Sankyo Co., Ltd, Tokyo, Japan. This study was also supported by the Japan Health Sciences Foundation [Grants-in-Aid for Public-private sector joint research on Publicly Essential Drugs (KHB 1208)].

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Yuichiro Imamura
    • 1
  • Nobuyuki Murayama
    • 1
  • Noriko Okudaira
    • 1
  • Atsushi Kurihara
    • 1
  • Katsuhisa Inoue
    • 2
  • Hiroaki Yuasa
    • 2
  • Takashi Izumi
    • 1
  • Hiroyuki Kusuhara
    • 3
  • Yuichi Sugiyama
    • 4
    Email author
  1. 1.Drug Metabolism & Pharmacokinetics Research Laboratories, R&D DivisionDaiichi Sankyo Co., LtdTokyoJapan
  2. 2.Department of Biopharmaceutics Graduate School of Pharmaceutical SciencesNagoya City UniversityNagoyaJapan
  3. 3.Laboratory of Molecular Pharmaceutics Graduate School of Pharmaceutical SciencesUniversity of TokyoTokyoJapan
  4. 4.Sugiyama Laboratory, RIKEN Innovation Center Research Cluster for Innovation, RIKENThe Institute of Physical and Chemical ResearchYokohama CityJapan

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