Flucytosine kinetics in subjects with normal and impaired renal function

Kinetics and bioavailability of flucytosine were studied in 5 subjects with normal renalfunction. Kinetic parameters and absorption were compared after a 500-mg dose administered in the following manner: intravenously, aqueous solution, and capsules while fasting; capsules after meals; and capsules with antacid. Encapsulation, food, and antacid decreased the absorption rate constant but the total amount absorbed orally did not differ significantly. Bioavailability assessed by the urinary recovery or comparison of the AUCo to AUCiv on the average showed 76% to 89% oral absorption. In 3 patients on hemodialysis, the serum concentrations in the β-phase following oral flucytosine in capsules during fasting were in the same range as those after a comparable intravenous dose. The mean steady-state distribution volume (Vdss) was 0.679 L/kg in normal subjects and ranged between 0.413 and 0.706 L/kg in 9 patients with renal failure. The mean t½β was 4.2 hr in normal subjects and the renal clearance was comparable to creatinine clearance. In renal failure, a linear regression analysis showed the t½β (hr) to be numerically about 5 times the steady-state serum creatinine concentration (mg/dl). Under the conditions of the study, hemodialyzer clearance of flucytosine was rapid and similar to creatinine hemodialyzer clearance. Computer simulation based on the measured pharmacokinetic parameters demonstrated that a loading dose (20 mg/kg) after dialysis should result in therapeutic plasma concentrations for susceptible organisms and avoid toxic levels.