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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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.
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.
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).
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 WORDSCYP3A4 drug-drug interaction mechanism-based inhibition (MBI) renal drug transporter tubular secretion
area under the concentration-time curve
brush border membrane
maximum plasma concentration
human embryonic kidney
human liver microsomes
degradation rate constant (turnover rate constant) of liver CYP3A4
multiple reaction monitoring
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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