Pharmacological studies with 5-fluorocytosine

Area of Science:

• Pharmacology
• Clinical Chemistry
• Mycology

Background:

• 5-fluorocytosine (5-FC) is an antifungal agent often used with amphotericin B.
• Accurate measurement of 5-FC is crucial for therapeutic drug monitoring, especially in patients with compromised renal function.
• Existing bioassays may not be suitable for determining 5-FC levels in the presence of amphotericin B.

Purpose of the Study:

• To describe a novel cylinder plate bioassay for quantifying 5-fluorocytosine (5-FC) in biological fluids.
• To evaluate the impact of renal function on 5-FC serum concentrations.
• To determine 5-FC concentrations in cerebrospinal fluid (CSF).

Main Methods:

• Development of a cylinder plate bioassay for 5-FC detection.
• Measurement of serum 5-FC concentrations in patients receiving single or multiple doses.
• Assessment of 5-FC levels in patients with varying degrees of renal function, including those with amphotericin B-induced renal insufficiency.
• Pharmacokinetic studies in rabbits with experimentally induced acute renal failure.
• Determination of 5-FC concentrations in CSF.

Main Results:

• The developed bioassay successfully measures 5-FC in biological fluids, even with amphotericin B present.
• Serum 5-FC was detectable up to 24 hours post-dose, with peak concentrations shifting earlier in patients on prolonged therapy.
• Renal impairment markedly increased peak 5-FC serum concentrations (up to 142% increase) and prolonged its half-life in rabbits (from ~3.4 to ~24.6 hours).
• CSF 5-FC concentrations ranged from 17 to 62 µg/ml, representing 74.4% of simultaneous serum levels.
• The effect of renal function on CSF 5-FC mirrored that observed in serum.

Conclusions:

• A reliable bioassay for 5-FC has been established, facilitating its therapeutic drug monitoring.
• Renal function significantly influences 5-FC pharmacokinetics, necessitating dose adjustments in patients with impaired kidney function.
• 5-FC penetrates the cerebrospinal fluid, suggesting potential efficacy in treating central nervous system fungal infections.