Influence of rifampin on fleroxacin pharmacokinetics.
Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7 days. On days 5 to 7 of rifampin treatment, 400 mg of fleroxacin was again administered once daily. Concentrations of fleroxacin as well as its two major urinary metabolites, N-demethyl- and N-oxide-fleroxacin, in plasma and urine were determined by reverse-phase high-performance liquid chromatography. The extent of hepatic enzyme induction by rifampin was confirmed by a significant increase of 6-beta-hydroxycortisol urinary output from 160.8 +/- 41.4 to 544.8 +/- 120.7 micrograms/4 h. There were no significant changes in the peak fleroxacin concentration in plasma (6.3 +/- 1.2 versus 6.2 +/- 1.9 mg/liter), time to maximum concentration of fleroxacin in plasma (1.1 +/- 0.9 versus 1.3 +/- 1.1 h), or renal clearance (58.3 +/- 16.4 versus 61.9 +/- 19.2 ml/min). The area under the curve AUC (71.4 +/- 15.8 versus 62.2 +/- 13.7 mg.h/liter) and the terminal half-life of fleroxacin (11.4 +/- 2.2 versus 9.2 +/- 1.1 h) decreased (P < 0.05), while the total plasma clearance increased from 97.7 +/- 21.6 to 112.3 +/- 25.8 ml/min (P < 0.01). Despite being statistically significant, this 15% increase in total plasma clearance does not appear to be clinically relevant. Metabolic clearance by N demethylation was increased ( 6.9 +/- 2.4 versus 12.5 +/- 3.2 ml/min; P < 0.01), whereas clearance by N oxidation did not change (5.8 +/- 1.1 versus 5.8 +/- 1.5 ml/min). Fleroxacin elimination was slightly increased (about 15%) through induction of metabolic clearance to N-demethyl-fleroxacin. Since fleroxacin levels remained above the MIC for 90% of the tested isolates of methicillin-susceptible S. aureus for at least 24 h, dose adjustment does not appear necessary, at least for short-term treatments.
Schrenzel
J
J
Division of Infectious Diseases, Geneva University Hospital, Switzerland.
Dayer
P
P
Leemann
T
T
Weidekamm
E
E
Portmann
R
R
Lew
D P
DP
D000328:Adult; D000900:Anti-Bacterial Agents; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000494:pharmacology; D004790:Enzyme Induction; D016576:Fleroxacin / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D012293:Rifampin / Q000009:adverse effects / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy
D000900:Anti-Bacterial Agents; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; D016576:Fleroxacin; D012293:Rifampin; D006854:Hydrocortisone