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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

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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.

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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

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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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Authors and Affiliations

  1. Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan

    Yuichiro Imamura, Nobuyuki Murayama, Noriko Okudaira, Atsushi Kurihara & Takashi Izumi

  2. Department of Biopharmaceutics Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan

    Katsuhisa Inoue & Hiroaki Yuasa

  3. Laboratory of Molecular Pharmaceutics Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Hiroyuki Kusuhara

  4. Sugiyama Laboratory, RIKEN Innovation Center Research Cluster for Innovation, RIKEN, The Institute of Physical and Chemical Research, 1-6 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan

    Yuichi Sugiyama

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  1. Yuichiro Imamura
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  2. Nobuyuki Murayama
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  3. Noriko Okudaira
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  4. Atsushi Kurihara
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  5. Katsuhisa Inoue
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  6. Hiroaki Yuasa
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  9. Yuichi Sugiyama
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Correspondence to Yuichi Sugiyama.

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Imamura, Y., Murayama, N., Okudaira, N. et al. 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. Pharm Res 30, 447–457 (2013). https://doi.org/10.1007/s11095-012-0890-6

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  • DOI: https://doi.org/10.1007/s11095-012-0890-6

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