Abstract
Elevated plasma concentrations of non-esterified fatty acids (NEFA) have been associated with lipotoxicity, ectopic fat deposition in organs and tissues (liver, skeletal muscle, pancreas), chronic heart failure, suppressed growth hormone secretion, and ventricular arrhythmias. A long-term clinical experience indicates that niacin (nicotinic acid) produces beneficial effects on dyslipidemias and slows down progression of atherosclerotic cardiovascular disease.
One of the mechanisms of the hypolipidemic effect of niacin is reduction of NEFA release from adipose tissue into free circulation, which is mediated by activated HCA2 receptors in adipocytes. To study plasma concentrations of niacin and its metabolites in relation to plasma NEFA changes.
Plasma concentrations of niacin, its metabolites, and NEFA were assessed in 12 healthy subjects (5 M/7 F) of middle age (44.2 +- 12.5 years), after a single oral dose of 500 mg of niacin (Niaspan(R)), applied on three successive days. After the third dose, niacin and its metabolites were determined by a HPLC- MS method, NEFA by an enzymatic-colorimetric method.
The dependency of changes in niacin, niacin metabolites and NEFA concentrations was studied using a stepwise multiple linear regression analysis. The relationship of the cutaneous flushing with the effects of niacin was assessed using and a linear mixed-effects model and a stepwise linear regression analysis.
Plasma concentrations of NEFA have significantly decreased between the first and sixth hour after niacin administration (P < 0.001). The variance of the declines in NEFA depended by 81.4 % on the variance of three compounds, namely N-methyl-nicotinamide (48.0 %), nicotinic acid (21.8 %), and 2-methyl-2-pyridon-carboxamide (11.6 %).
Cutaneous flushing has occurred in four subjects (25 %). The occurrence of flushing was associated with lower concentrations of nicotinuric acid (-60 %, P < 0.05).
Subjects with flushing revealed the higher decrease in NEFA in comparison with subjects without skin toxicity (P < 0.05). The antilipolytic effect of niacin (decrease in NEFA) was mainly mediated by the metabolite N- methyl-nicotinamide; its relation to undesirable skin changes is controversial.