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.
OBJECTIVE
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).
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
Yuichiro
Y
Imamura
Nobuyuki
N
Murayama
Noriko
N
Okudaira
Atsushi
A
Kurihara
Katsuhisa
K
Inoue
Hiroaki
H
Yuasa
Takashi
T
Izumi
Hiroyuki
H
Kusuhara
Yuichi
Y
Sugiyama
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011759:Pyrrolidines / Q000378:metabolism*; D015363:Quinolones / Q000378:metabolism*
D000900:Anti-Bacterial Agents; C505440:DX 619; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011759:Pyrrolidines; D015363:Quinolones; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; C114338:organic anion transport protein 3; C001380:6 beta-hydroxycortisol; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone