Vol. 284, Issue 1, 337-345, 1998

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

Stuart L. Bursten, David Federighi, Jeffrey Wald, Brent Meengs, William Spickler and Edward Nudelman

Cell Therapeutics, Inc., Division of Lipid Biology and Analytical Lipid Biochemistry, Seattle, Washington (S.L.B., D.F., B.M., W.S., E.N.) and Quintiles, Inc., Research Triangle Park, North Carolina (J.W.)

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 < .01 vs. 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.