Lisofylline Causes Rapid and Prolonged Suppression of Serum Levels of Free Fatty Acids1

Abstract

Lisofylline (LSF), a novel anti-inflammatory compound that modulates stress-associated changes in lipid metabolism, is under development to modify toxicity for patients undergoing dose-intensive cytotoxic therapy for neoplasia and to prevent multiorgan failure and acute respiratory distress syndrome after oxidative injury. The present investigation, a component of a pharmacokinetics study, was performed to assess the effect of LSF on serum-free fatty acids (FFA). LSF was administered at doses of either 1, 2 or 3 mg/kg every 24 hr for 3 days by 10 min intravenous infusion to 12 healthy volunteers, followed 24 hr later by a single oral dose of 6 mg/kg, which was determined not to be bioavailable. Total serum FFA were quantitated after separation from other lipids by thin-layer chromatography in samples from 10 of 12 subjects, and serum levels of individual fatty acids were measured by high-performance liquid chromatography in samples from 11 of 12 subjects. Six hours after the first LSF dose of 1, 2 or 3 mg/kg, FFA levels decreased from the time zero levels by a mean (±S.D.) of 64.7 ± 7.4% (range, 37–80%; P < .001 vs. time zero levels). Six hours after the third i.v. LSF dose, the FFA reached a nadir of 71.5 ± 5.5% below the time zero levels (range, 55–88%; P < .001 vs. time zero). Equivalent effects were observed after the first LSF dose regardless of whether patients received LSF at 1, 2 or 3 mg/kg. The decrease in serum FFA was still present 48 hr after the final i.v. dose and 24 hr after the oral dose, with a mean decrease of 34 ± 9.8% (P < .01vs. time zero). Serum triglycerides began to increase after the first i.v. LSF dose and were at the highest measured level 6 hr after the third dose, increasing by 74.5 ± 19.7% from the time zero levels (range, 36–146%; P = .02 vs. time zero). The increase in serum triglycerides also persisted for 36 hr after the final i.v. LSF dose. LSF and its two principal metabolites had plasma clearance t_1/2 values of 0.75 hr, 0.78 hr and 1.17 hr, respectively. Therefore the effects of LSF on lipid metabolism were present for a prolonged period compared with measurable persistence in plasma; this points to unique functions or unknown metabolites of LSF. These alterations in serum lipids may be relevant to the anti-inflammatory activity of LSF and may serve as surrogate markers for the pharmacodynamics of LSF.