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

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 clea...

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Published in:Pharmaceutical research 2013-02, Vol.30 (2), p.447-457
Main Authors: Imamura, Yuichiro, Murayama, Nobuyuki, Okudaira, Noriko, Kurihara, Atsushi, Inoue, Katsuhisa, Yuasa, Hiroaki, Izumi, Takashi, Kusuhara, Hiroyuki, Sugiyama, Yuichi
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - metabolism
Antibacterial agents
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Cytochrome P-450 CYP3A - metabolism
Female
HEK293 Cells
Humans
Hydrocortisone - analogs & derivatives
Hydrocortisone - metabolism
Hydrocortisone - urine
Male
Medical Law
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Organic Anion Transport Protein 1 - metabolism
Organic Anion Transporters, Sodium-Independent - metabolism
Organic Cation Transport Proteins - metabolism
Organic Cation Transporter 2
Pharmacology/Toxicology
Pharmacy
Pyrrolidines - metabolism
Quinolones - metabolism
Research Paper
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Summary: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 (CL 6β−OHF and CL renal,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 K I and k inact 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. CL 6β−OHF and CL renal,6β−OHF were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo ( P  
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-012-0890-6