Differences in metabolism of time-release and unmodified nicotinic acid: explanation of the differences in hypolipidemic action?
The possibility that differences in metabolism might underly the differences in efficacy and toxicity between time-release and unmodified formulations of nicotinic acid was investigated by measuring 24-hour urinary excretion of metabolites in 10 subjects who received both forms. Nicotinic acid has two metabolic fates: formation of nicotinamide adenine dinucleotide (NAD) and formation of nicotinuric acid, the glycine conjugate of nicotinic acid. Catabolism of NAD releases nicotinamide, which is subsequently methylated and/or oxidized to form a number of metabolites, with 2-pyridone predominating. Excretion of nicotinuric acid was more than four times greater when subjects took unmodified nicotinic acid than when they took time-release nicotinic acid (78.2 and 18.8 mg, respectively). In contrast, excretion of 2-pyridone with unmodified nicotinic acid was only 30% more than with time-release nicotinic acid (171.0 and 129.9 mg, respectively). These results demonstrate a marked difference in the metabolism of unmodified and time-release nicotinic acid. It is proposed that nicotinyl coenzyme A (CoA), the metabolic intermediate in the formation of nicotinuric acid, mediates some of the hypolipidemic actions of nicotinic acid, as the acyl-CoA esters of xenobiotics, including clofibrate, have been shown to interfere with lipid metabolism.
Stern
R H
RH
Department of Medicine, University of Western Ontario, London, Canada.
Freeman
D
D
Spence
J D
JD
D000328:Adult; D000704:Analysis of Variance; D003692:Delayed-Action Preparations; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D009525:Niacin / Q000493:pharmacokinetics* / Q000652:urine; D009539:Nicotinic Acids / Q000652:urine; D011728:Pyridones / Q000652:urine
D003692:Delayed-Action Preparations; D008055:Lipids; D009539:Nicotinic Acids; D011728:Pyridones; D009525:Niacin; C002477:nicotinuric acid