3 times a day).
Niacin IR has beenapproved by the US Food and Drug Administration (FDA) for the treatment of dyslipidemias and is available over thecounter.In an attempt to reduce flushing, sus-tained-release (SR) niacin formulationswere developed in the 1960s. The clinicaluse of some of these products, however,has suggested an increased incidence of hepatotoxicity and gastrointestinal intol-erance.
The studies reviewed in this arti-cle demonstrate that although niacin SR reduces flushing and itching, it has incon-sistent effects on lipoprotein parametersand is associated with an increased risk for various side effects. Sustained-releaseformulations, which are not FDA approvedfor the treatment of dyslipidemia, are usu-ally sold over the counter as health foodsupplements.Niacin extended-release (ER), a recent-ly introduced intermediate-release niacinformulation, has a unique delivery systemthat allows drug absorption over 8 to 12hours. This formulation was developed inan attempt to achieve the lipid-loweringefficacy of niacin IR with a reduced inci-dence of flushing and to minimize thehepatotoxicity seen with longer-acting for-mulations. Niacin ER is FDA approved forthe treatment of dyslipidemia and is avail-able by prescription only.
Pharmacokinetics of Niacin
An understanding of the differences inside effect profiles of niacin IR, SR, and ER requires a review of the pharmacokineticsof niacin. Niacin undergoes extensive, sat-urable, first-pass metabolism in the liver,where it is metabolized by 2 hepatic path-ways (
). In one pathway, niacin isconjugated with glycine to form nicotin-uric acid. This conjugative pathway is alow-affinity, high-capacity pathway thatgenerates metabolites that are associatedwith flushing. The second pathway involvesseveral general oxidation-reduction meta-bolic reactions that produce nicotinamideand a series of related products, such asnicotinamide adenine dinucleotide, andultimately several pyrimidinemetabolites.This amidation, or nonconjugative, path-way is a high-affinity, low-capacity path-way with metabolites that are associatedwith hepatotoxicity.
Thus, the absorptionrates of the different formulations dictatethe extent of metabolism by each pathway,the type of metabolites generated, and theside effect profile. Niacin IR is usually com-pletely absorbed within 1 to 2 hours;niacin SR absorption rates vary from prod-uct to product and even batch to batch,but generally exceed 12 hours.
Niacin ER has an absorption rate of 8 to 12 hours.
Niacin IR quickly saturates the amidationpathway, resulting in most of the drugbeing metabolized by the conjugative path-way and thereby causing a high incidenceof flushing. Conversely, niacin SR ismetabolized to a greater extent by the ami-dation pathway, saturating it more slowly. As a result, niacin SR has a lower inci-dence of flushing, but a higher incidence of hepatotoxicity.
Niacin ER, with its inter-mediate dissolution rate, better balancesmetabolism along the 2 pathways, result-ing in a lower rate of flushing and hepaticeffects compared with niacin IR and niacinSR, respectively.The differences in metabolism andrelated side effects can be most clearly
VOL. 8, NO. 12, SUP.THE AMERICAN JOURNAL OF MANAGED CARE
Understanding Niacin Formulations
The Metabolic Pathways of Niacin
Glycine conjugate(flushing)Amidation pathway(hepatotoxicity)NUA NAM6HN NNO MNA NAD2PY 4PYONCOH
NUA indicates nicotinuric acid; NAM, nicotinamide;6HN, 6-hydroxynicotinamide; NAD, nicotinamide ade-nine dinucleotide; MNA, N-methylnicotinamide; NNO,nicotinamide-N-oxide; 2PY, N-methyl-2-pyridone-5-car-boxamide; 4PY, N-methyl-4-pyridone-5-carboxamide.
Used with permission from Piepho RW. Thepharmacokinetics and pharmacodynamics of agentsproven to raise high-density lipoprotein cholesterol.
Am J Cardiol.