Pharmacokinetics, safety, and tolerability of flosequinan in patients with hepatic dysfunction.
The pharmacokinetics of flosequinan and its active metabolite, flosequinoxan, were investigated following a single 100-mg oral dose in 10 patients with compromised hepatic function. Plasma and urine samples were collected for up to 144 h postdose and analyzed by HPLC. All 10 patients provided analyzable data even though one patient withdrew before the 144-h sample because of an adverse event unrelated to the study medication. Interpatient variability was appreciable for the plasma and urine concentrations was well as for the calculated pharmacokinetic parameters. Relative to a comparative cohort of normal subjects, flosequinan concentrations in the study patients were elevated, showing increases in mean AUC0-t (62.8 +/- 49.4 vs 3.4 +/- 1.5 micrograms.h/mL), AUC0-infinity (70.2 +/- 58.3 vs 3.8 +/- 1.6 micrograms.h/m:), Cmax (2.43 +/- 0.56 vs 1.30 +/- 0.39 micrograms/mL), and t1/2 (20.7 +/- 16.8 vs 1.7 +/- 0.5 h). The mean systemic clearance decreased (47.3 +/- 46.5 vs 544 +/- 279 mL/min), along with the elimination rate constant (0.066 +/- 0.069 vs 0.44 +/- 0.13 h-1). Mean flosequinoxan AUC0-t and AUC0-infinity values were unaffected by hepatic dysfunction. The mean time to peak was longer (36.4 +/- 27.4 vs 7.0 +/- 3.1 h) and Cmax was less (0.98 +/- 0.52 vs 1.84 +/- 0.26 micrograms/mL) than in normal subjects. These findings are consistent with a decrease in the rate of flosequinan metabolism to flosequinoxan. Five patients reported adverse events, which included headache (three patients) and syncope (one patient).(ABSTRACT TRUNCATED AT 250 WORDS)
Hinson
J L
JL
Boots Pharmaceuticals, Inc., Shreveport, LA 71136.
Hind
I D
ID
Weidler
D J
DJ
D000328:Adult; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D015363:Quinolones / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet
D011804:Quinolines; D015363:Quinolones; C047316:flosequinan; C047317:flosequinoxan