DETERMINATION OF FOSTRIECIN PHARMACOKINETICS IN PLASMA USING HIGH-PRESSURE LIQUID-CHROMATOGRAPHY ASSAY

Fostriecin is an antitumor antibiotic with marked activity against ova rian, breast, and lung cancer cell lines in the human tumor clonogenic assay. The mechanism of cytotoxicity in vivo is unknown; in vitro it has been shown to inhibit macromolecular synthesis, interact with the reduced folate carrier system, and inhibit topoisomerase II. Phase I t esting of fostriecin in a daily for 5 days schedule has begun in cance r patients. A high-pressure liquid chromatographic method to measure f ostriecin in plasma samples was developed using sulfaquinoxaline as an internal standard and ultraviolet detection (268 nm). The extraction efficiency is 70% and the sensitivity limit is 100 ng/ml. The pharmaco kinetics of fostriecin were determined in six rabbits following intrav enous injection of 12 mg/m2. The mean distribution space was 4.44 L/m2 and the mean plasma clearance was 302 ml/min/m2. The elimination half -life was 11.95 +/- 8.55 min. All rabbits exhibited a 10-60-fold incre ase in aspartate aminotransferase (AST) and alanine aminotransferase ( ALT) that resolved within 48 h of drug administration.