Effect of the Rate of Niacin Administration on the Plasma and Urine Pharmacokinetics of Niacin and Its Metabolites

Abstract

The metabolic profile of niacin is influenced by the rate of niacin administration. This study characterizes the effect of administration rate on the pharmacokinetics of niacin and its metabolites. Twelve healthy males were enrolled in an open-label, dose-rate escalation study and received 2000 mg niacin at 3 different dosing rates. Plasma was analyzed for niacin, nicotinuric acid, nicotinamide, and nicotinamide-N-oxide. Urine was analyzed for niacin and the metabolites nicotinuric acid, nicotinamide, nicotinamide-N-oxide, N-methylnicotinamide, and N-methyl-2-pyridone-5-carboxamide. C(max) and AUC(0-t) for niacin and nicotinuric acid increased with an increase in dosing rate. The changes observed in plasma nicotinamide and nicotinamide-N-oxide parameters, however, did not correlate to dosing rate. The total amount of niacin and metabolites excreted in urine was comparable for all 3 treatments. However, with the increase in dosing rate, urine recovery of niacin and nicotinuric acid showed a significant increase, whereas N-methyl-2-pyridone-5-carboxamide and N-methylnicotinamide showed a significant decrease.

Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease

“…The concentrations of niacin (0.25-0.5 mmol/L) used in our in-vitro studies are clinically relevant and comparable to the niacin concentrations observed in human plasma and probably in the liver after oral administration of niacin in clinical doses. In humans, plasma level of niacin was found to be about 0.3 mmol/L after oral ingestion of 2 g of niacin [52], and high plasma concentrations of niacin are also corroborated by a recent study [53]. Also because of the first pass effect and transport through the portal venous system, niacin concentrations in liver tissue will be much higher than in plasma levels after oral administration of 1-3 g of niacin.…”

“…Whereas immediate-release niacin produces more flushing, hepatotoxicity is increased with the use of very slow-release preparation in the past [53]. Recently available agents have been developed as extended-release preparations with an optimized intermediate-release rate so that flushing and hepatotoxicity are minimized [52,54]. The most significant side effect is the niacin flush, a prostaglandin D2-mediated vaso-cutaneous reaction (reviewed in [55]).…”

Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells

“…In this study, we have used niacin at doses of 0.1-1.0 mM for incubation with HepG2 cells. In humans, plasma level of niacin was found to be about 0.3 mM after oral ingestion of 2 g of niacin ( 32 ). In our extensive clinical experience with niacin, the plasma concentrations of niacin will be in the range of 0.1-0.5 mM after oral administration of 1-3 g doses of niacin (the dose commonly used in humans).…”

Dietary methyl-consuming compounds and metabolic syndrome

“…Nicotinic acid can be either converted to nicotinamide and then degraded via the nicotinamide catabolic pathway (methyl-consuming catabolic pathway), or excreted in the urine unchanged and as nicotinuric acid (non-methyl-consuming catabolic pathway). 47 In contrast, nicotinamide is rarely excreted into the urine in its original form due to a high rate of tubular reabsorption. 48 Thus, equivalent doses of nicotinamide may consume more methyl groups than nicotinic acid.…”

“…It has shown that nicotinamide at physiological concentrations is degraded mainly via the methyl-consuming mechanism, 61 and that the appearance of nonmethylated metabolites of nicotinamide in urine indicates nicotinamide overload and toxicity. 47,62 Most importantly, long-term highlevel niacin exposure has been observed to induce a methyl-group deficiency state and fatty liver due to an increased need for methylation of niacin in animal studies. 55,63 Based on current evidence, it seems likely that increases in niacin consumption may be correlated to the following phenomena: (1) the prevalence of T2D in the United States has increased in parallel with the increase in per capita consumption of niacin-fortified grains since the implementation of niacin fortification, whereas traditional high intake of non-fortified grain is associated with very low rates of obesity and diabetes; 34 (2) the prevalence of metabolic syndrome-related diseases in niacin-fortified countries is much higher than that of non-fortified developed countries; 34 (3) high consumption of meat, a nicotinamide-rich food, may increase the risk for metabolic syndrome; 64 and (4) consumption of processed meat, in which niacin is used in meat coloring in some non-European countries, can significantly increase the risk of T2D.…”