The Kinetics of 5-Fluorocytosine Elimination in Man

It is important that serum levels of 5-fluorocytosine (5FC) be measured to insure therapeutic levels while avoiding toxicity. This is particularly true in patients with renal insufficiency. The concurrent use of amphotericin B and 5FC complicates the measurement of 5FC in the serum, since fungi used in conventional bioassay systems are uniformly susceptible to amphotericin B. This paper describes the development of a simple, reliable, 6-h bioassay for 5FC in the presence of amphotericin B. The assay is based upon the fact that 5FC diffuses readily through yeast nitrogen base agar, whereas amphotericin B apparently does not. This assay allows rapid adjustments in therapy of patients receiving both 5FC and amphotericin B and has permitted us to maintain 5FC serum levels between limits of 25 and 120 ,g/ml in patients with altered renal function.

Section: Resultssupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Rapid, Simple Bioassay for 5-Fluorocytosine in the Presence of Amphotericin B

Kaspar

Drutz

1975

“…Renal function assumes a very important role in determining serum levels and subsequent toxicity of 5-FC since this drug is excreted almost wholly by the kidneys (16). In the face of rapidly progressive renal failure, as in patient 1, very high serum levels of 5-FC can occur and persist for several days even though the drug has been discontinued.…”

Section: Fourmentioning

confidence: 99%

“…To avoid toxicity during combined therapy, 5-FC serum concentration and serum creatinine should be monitored closely and the dosage of 5-FC adjusted accordingly. Several methods of adjusting the dosage of 5-FC on the basis of creatinine clearance have been proposed (12,16). Use of such formulas combined with determination of 5-FC serum concentrations should obviate the problem of 5-FC-related marrow toxicity.…”

Section: Fourmentioning

confidence: 99%

Bone Marrow Toxicity Associated with 5-Fluorocytosine Therapy

Kauffman

Frame

1977

143

Bone marrow toxicity occurred in 4 of 15 patients treated with 5-fluorocytosine (5-FC) for serious fungal infections. The development of marrow toxicity appeared to be related to serum 5-FC levels of 125 ,g/ml or greater. In three patients, accumulation of toxic levels of 5-FC was related to diminished renal function. One patient with acute renal failure and prolonged high levels of 5-FC developed marrow aplasia and died of bacterial sepsis. Three patients experienced leukopenia, which was readily reversed when the dosage of 5-FC was decreased and the serum concentration was lowered. With careful monitoring of serum 5-FC concentration and renal function, the dose-related toxic effects of 5-FC on the marrow can be avoided.

“…Because of its nephrotoxic effects, administration of AmB frequently leads to a diminished creatinine clearance (10). 5-FC is excreted almost entirely by the kidneys (12). In the face of decreasing renal function, excessively high levels of 5-FC may accumulate.…”

mentioning

confidence: 99%

Simple Assay for 5-Fluorocytosine in the Presence of Amphotericin B

Kauffman

Carleton²,

Frame³

1976

A simple method for the measurement of 5-fluorocytosine in the presence of amphotericin B is described. The antifungal activity of amphotericin B is abolished by heating serum at 100 C for 45 min. 5-Fluorocytosine is unaffected by this treatment, and serum levels can be subsequently assayed by either tube dilution or disk diffusion methods.Combined drug therapy with amphotericin B (AmB) and 5-fluorocytosine (5-FC) has potential usefulness in the treatment of severe fungal infections caused by Cryptococcus neoformans, Torulopsis glabrata, and Candida species (1, 11). Because of its nephrotoxic effects, administration of AmB frequently leads to a diminished creatinine clearance (10). 5-FC is excreted almost entirely by the kidneys (12). In the face of decreasing renal function, excessively high levels of 5-FC may accumulate. To avoid the potentially toxic effects of 5-FC on the bone marrow and other organs (3,4,6,7,11), it is imperative that 5-FC levels be monitored closely in patients on combination therapy. Block and Bennett have described a method involving separation of 5-FC and AmB by ultrafiltration, allowing quantitation of serum 5-FC levels (3). Kaspar and Drutz have used differential diffusion rates of AmB and 5-FC as a means of assaying for 5-FC in the presence of AmB (5). Reported herein is a simple method of heat inactivation of AmB so that levels of 5-FC can be accurately assayed during combined therapy with both drugs.MATERIALS AND METHODS Preparation of standards. A stock solution of 1,000 ,ug of AmB (E. R. Squibb & Sons, Princeton, N.J.) per ml was prepared in sterile distilled water. The 5-FC (Hoffmann-La Roche, Inc., Nutley, N.J.) stock solution, 1,000 ug/ml, was prepared in 0.85% saline. Further dilutions of these standards were prepared with pooled human sera in saline so that a final concentration of 10% serum was achieved.Effect of heat on antifungal activity of AmB and 5-FC. Standard solutions, prepared as described above in 10% human serum, were heated at different temperatures for varying lengths of time. The temperatures employed were 37, 56, 100 (achieved by using flowing steam at 0 lb/in2 in a standard autoclave), and 121 C (21 lb/in2). The antifungal activity of each drug was then tested by the tube dilution method outlined below.