The pharmacokinetics of flosequinan and its major active metabolite (BTS 53,554, 7-fluoro-1-methyl-3 methylsulfinyl-4-quinolone, 1) were investigated following a single oral dose of 100 mg of flosequinan in 20 patients with severe renal dysfunction (creatinine clearance, < or = 25 mL/min). Plasma and urine samples were collected for 144 h post-dose and analyzed by high-performance liquid chromatography. Flosequinan was well absorbed and rapidly eliminated, reaching mean peak concentrations in plasma of 1.37 +/- 0.67 micrograms/mL at 1.6 +/- 1.4 h post-dose. As in healthy volunteers, approximately 1% of the administered dose of flosequinan was excreted unchanged in urine. Renal clearance of flosequinan was decreased by an average of 20% relative to healthy volunteers. The active metabolite 1 reached mean peak concentrations in plasma of 2.22 +/- 0.58 micrograms/mL at 10.9 +/- 5.9 h post-dose and yielded mean areas under the curve of concentration in plasma versus time twice that of healthy volunteers. Elimination rates for 1 decreased by half, and the mean elimination half-life increased to 68.5 +/- 24.2 h compared with 34.5 +/- 6.7 h for healthy volunteers. The decrease in elimination rate resulted in higher exposure to total active drug substance (flosequinan plus metabolite) for renal patients than for healthy volunteers. These results suggest dosage adjustments may be necessary in patients with severe renal dysfunction to prevent excessive accumulation of 1 with repeated dosage of flosequinan.