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

• Published in: Pharmaceutical research Vol. 30; no. 2; p. 447
• Main Authors: Imamura, Yuichiro, Murayama, Nobuyuki, Okudaira, Noriko, Kurihara, Atsushi, Inoue, Katsuhisa, Yuasa, Hiroaki, Izumi, Takashi, Kusuhara, Hiroyuki, Sugiyama, Yuichi
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01.02.2013
• Subjects: Antibiotics; Inhibitor drugs; Kidneys; Metabolism; Pharmaceutical sciences; Pharmacology
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-012-0890-6

To examine the effect of the fluoroquinolone DX-619 on CYP3A4 and urinary excretion of 6[beta]-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 6[beta]-hydroxycortisol (CL^sub 6β-OHF^ and CL^sub renal,6β-OHF^, respectively) were determined in placebo- and DX-619-treated subjects. 6[beta]-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 K^sub i^ and k^sub inact^ of 67.9±7.3 μmol/l and 0.0730±0.0033 min^sup -1^, respectively. Pharmacokinetic simulation suggested in vivo relevance of CYP3A4 inhibition by DX-619. CL^sub 6β-OHF^ and CL^sub renal,6β-OHF^ were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo (P<0.05). 6[beta]-hydroxycortisol was a substrate of OAT3 (K^sub m^=183±25 μmol/l), OCT2, MATE1, and MATE2-K. Maximum unbound concentration of DX-619 (9.1±0.4 μmol/l) was above K^sub i^ 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 6[beta]-hydroxycortisol into urine. Caution is needed in applying CL^sub 6β-OHF^ as an index of hepatic CYP3A4 activity without evaluating CL^sub renal,6β-OHF^.[PUBLICATION ABSTRACT]