The Pharmacokinetics of Nicotinamide in Humans and Rodents

Author:

Petley Ann12,Macklin Beryl3,Renwick Andrew G3,Wilkin Terence J12

Affiliation:

1. Department of Medicine, University of Southampton Southampton, United Kingdom

2. University of Plymouth, Plymouth; and University Medicine, University of Southampton Southampton, United Kingdom

3. Clinical Pharmacology, University of Southampton Southampton, United Kingdom

Abstract

Nicotinamide, a derivative of the B vitamin niacin, is currently under trial for the prevention of insulin-dependent diabetes mellitus after success in the NOD mouse. However, the dose, route of administration, and formulation of nicotinamide given to humans is quite different from those used successfully in animals, and the aim of this study was to investigate the plasma pharmacokinetics of oral nicotinamide in humans in two doses and in two different formulations (standard and the long-acting Enduramide). There were no significant differences in the kinetics of the low dose of standard nicotinamide (2.5 mg/kg) and low-dose Enduramide (6.7 mg/kg) in young adult men. Nonlinear kinetics were found with both formulations at higher doses, e.g., a 10-fold increase in the dose of the standard nicotinamide produced a 62-fold increase in the area under the plasma concentration-time curve (AUC). The high dose of standard nicotinamide (25 mg/kg body wt) produced a mean peak plasma concentration 75% higher than that achieved with the sustained release nicotinamide preparation given in a dose similar to that currently used in prevention trials (2 g ≡ 26.6 mg/kg body wt for a 75-kg subject). The AUC was also significantly greater with the standard formulation, indicating a higher bioavailability. Long-term plasma levels for high doses of both formulations were modeled from the single-dose kinetics by computer program. The AUC for standard nicotinamide was 1.7 times higher than that for Enduramide. We conclude that standard nicotinamide offers greater bioavailability than the long-acting formulation tested and that the metabolic clearance pathways of nicotinamide are saturated at the doses currently used in human trials.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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