THE PHARMACOKINETICS OF NICOTINAMIDE IN HUMANS AND RODENTS

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 fr om those used successfully in animals, and the aim of this study was t o investigate the plasma pharmacokinetics of oral nicotinamide in huma ns in two doses and in two different formulations (standard and the lo ng-acting Enduramide). There were no significant differences in the ki netics of the low dose of standard nicotinamide (2.5 mg/kg) and low-do se 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 curre ntly used in prevention trials (2 g = 26.6 mg/kg body wt for a 75-kg s ubject). The AUC was also significantly greater with the standard form ulation, 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 nic otinamide offers greater bioavailability than the long-acting formulat ion tested and that the metabolic clearance pathways of nicotinamide a re saturated at the doses currently used in human trials.