The Kinetics of 5-Fluorocytosine Elimination in Man

Abstract

Summary: 5-Fluorocytosine (5-FC) represents an important advance in the chemotherapy of cryptococcosis and some serious fungal diseases, especially systemic moniliasis. The drug is excreted mainly by the kidney and has a wide margin of safety, but potentially toxic high plasma levels follow normal dosage regimes in patients with renal insufficiency. Using 5-fluorocytosine-2-14C, the plasma and urinary clearances of 5-FC have been measured together with simultaneous inulin clearances. In eight healthy subjects we have demonstrated that the drug is eliminated largely by the kidney, an average of 90% of an intravenous load being recovered as unchanged drug in the urine within 48 hours. Following the intravenous load, the fall in plasma concentration is exponential with a half-time of 234.6 ‡24.8 minutes (SE). The drug is distributed widely in the body and not bound to plasma proteins. Evidence was obtained that 5-FC is excreted by filtration at the glomerulus without significant tubular reabsorption or secretion. Clearances calculated from the exponential plasma decay curves are greater than clearances calculated by standard methods from plasma concentration and urinary excretion rate, suggesting that some of the clearance from plasma is not due to renal elimination of free compound. No evidence was obtained that 5-FC is deaminated to 5-fluorouracil following administration by this route. A formula is presented to calculate 5-FC dosages in patients with renal insufficiency.