Inhibition of leukotriene synthesis, pharmacokinetics, and tolerability of a novel dietary fatty acid formulation in healthy adult subjects.
BACKGROUND
Numerous studies have explored dietary-management strategies for decreasing leukotriene synthesis by inflammatory cells through supplementation with polyunsaturated fatty acids such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA).


OBJECTIVE
This study sought to determine the optimal daily intake, ratios, and formulation of dietary GLA and EPA required to safely reduce leukotriene biosynthesis in healthy individuals, and to evaluate the pharmacokinetics and safety profile of such a formulation.


METHODS
Two preliminary trials were conducted to determine the minimum effective levels of GLA and EPA intake needed to reduce leukotriene biosynthesis and prevent increases in plasma arachidonic acid (AA) concentrations. These preliminary trials were followed by a single-center, randomized, double-blind, placebo-controlled, parallel-group, escalating-intake inpatient trial of a dietary GLA/EPA emulsion (PLT 3514) in healthy adult subjects. Subjects consumed either 10, 20, or 100 g of the PLT 3514 emulsion (respectively containing 0.75 g GLA + 0.5 g EPA, 1.5 g GLA + 1 g EPA, and 7.5 g GLA + 5 g EPA), or a placebo emulsion containing olive oil daily for 14 days. Plasma fatty acids were measured by gas chromatography Stimulated whole blood leukotrienes were measured by high-performance liquid chromatography with ultraviolet detection.


RESULTS
Thirty subjects were included in the preliminary trials; 47 subjects were enrolled in the escalating-intake trial, of whom 42 completed the study. In the preliminary trials, intake of GLA 1.5 g/d in gelatin capsules decreased the capacity to synthesize leukotrienes but increased plasma levels of AA (both, P < 0.05). Inclusion of 0.25 or 1 g of dietary EPA prevented the increase in plasma AA concentrations. Dietary GLA and EPA showed significantly enhanced bioavailability when consumed in 20 g PLT 3514 emulsion compared with consumption in gelatin capsules (P < 0.05), resulting in a reduction in the amount of intake required to block leukotriene biosynthesis. Pharmacokinetic analyses indicated that fasting plasma GLA and EPA levels plateaued within 7 days' daily consumption at all levels of intake, whereas the time to maximum plasma concentration (Tmax) was shorter for GLA than for EPA. The Tmax was similar on days 1 and 14 for both GLA and EPA. There were no clinically significant between-group differences in changes in vital signs, mean clinical laboratory values, or abbreviated hematology laboratory tests, or significant differences in the occurrence of treatment-emergent adverse events between the group consuming up to 20 g/d of the GLA/EPA emulsion and the group consuming placebo.


CONCLUSIONS
Consumption of specific proportions and intake levels of dietary GLA and EPA in a novel emulsion formulation inhibited leukotriene biosynthesis and appeared to be well tolerated in this population of healthy adult subjects.
Surette
Marc E
ME
Department of Research and Development, Pilot Therapeutics Inc., Charleston, South Carolina, USA. marcs@pilott.com
Koumenis
Iphigenia L
IL
Edens
Michelle B
MB
Tramposch
Kenneth M
KM
Chilton
Floyd H
FH
D000328:Adult; D000704:Analysis of Variance; D016718:Arachidonic Acid / Q000097:blood / Q000378:metabolism; D004311:Double-Blind Method; D015118:Eicosapentaenoic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D004655:Emulsions; D005227:Fatty Acids / Q000097:blood; D005231:Fatty Acids, Unsaturated / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D005526:Food, Formulated; D006261:Headache / Q000209:etiology; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D008297:Male; D009325:Nausea / Q000209:etiology; D016896:Treatment Outcome; D017965:gamma-Linolenic Acid / Q000493:pharmacokinetics / Q000494:pharmacology
D004655:Emulsions; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D007975:Leukotriene B4; D016718:Arachidonic Acid; D017965:gamma-Linolenic Acid; D015118:Eicosapentaenoic Acid