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. 2013 Feb;30(2):447-57. doi: 10.1007/s11095-012-0890-6. Epub 2012 Oct 17.

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 (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 < 0.05). 6β-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 6β-hydroxycortisol into urine. Caution is needed in applying CL(6β-OHF) as an index of hepatic CYP3A4 activity without evaluating CL(renal,6β-OHF).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / metabolism*
  • Cytochrome P-450 CYP3A / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • Hydrocortisone / analogs & derivatives*
  • Hydrocortisone / metabolism
  • Hydrocortisone / urine
  • Male
  • 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
  • Pyrrolidines / metabolism*
  • Quinolones / metabolism*

Substances

  • Anti-Bacterial Agents
  • DX 619
  • MATE1 protein, human
  • MATE2-K protein, human
  • Organic Anion Transport Protein 1
  • Organic Anion Transporters, Sodium-Independent
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • Pyrrolidines
  • Quinolones
  • SLC22A2 protein, human
  • organic anion transport protein 3
  • 6 beta-hydroxycortisol
  • Cytochrome P-450 CYP3A
  • Hydrocortisone