Effect of the fluoroquinolone antibacterial agent DX-619 on the apparent formation and renal clearances of 6ß-hydroxycortisol, an endogenous probe for CYP3A4 inhibition, in healthy subjects.

ABSTRACT

PURPOSE: To examine the effect of the fluoroquinolone DX-619 on CYP3A4 and urinary excretion of 6ß-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 6ß-hydroxycortisol (CL(6ß-OHF) and CL(renal,6ß-OHF), respectively) were determined in placebo- and DX-619-treated subjects. 6ß-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(6ß-OHF) and CL(renal,6ß-OHF) were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo (P < 0.05). 6ß-hydroxycortisol was a substrate of OAT3 (K(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(i) 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 6ß-hydroxycortisol into urine. Caution is needed in applying CL(6ß-OHF) as an index of hepatic CYP3A4 activity without evaluating CL(renal,6ß-OHF).