Pharmacokinetics of the SABRE agent 4,6-d2-nicotinamide and also nicotinamide in rats following oral and intravenous administration

To prepare the way for using the isotopically labelled SABRE hyperpolarized 4,6-d2-nicotinamide as an MRI agent in humans we have performed an in-vivo study to measure its pharmacokinetics in the plasma of healthy rats after intravenous and oral administration. Male Han Wistar rats were dosed with either 4,6-d2-nicotinamide or the corresponding control, non-labelled nicotinamide, and plasma samples were obtained at eight time points for up to 24 h after administration. Pharmacokinetic parameters were determined from agent concentration-versus-time data for both 4,6-d2-nicotinamide and nicotinamide. 4,6-d2-Nicotinamide proved to be well tolerated regardless of route of administration at the concentrations used (20, 80 and 120 mg/kg). Pharmacokinetic parameters were similar after oral and intravenous administration and similar to those obtained for nicotinamide. Analysis of nicotinamide plasma concentrations after dosing 4,6-d2-nicotinamide intravenously demonstrates a reversible exchange of endogenous nicotinamide by this labelled agent over the time-course of our assays. Supported by a large body of evidence for the safety of nicotinamide when dosed orally in humans, we conclude that 4,6-d2-nicotinamide can also be safely administered intravenously, which will provide significant benefit when using this agent for planned imaging studies in humans.
Graphical abstract Mean concentrations of (a) 4,6-d2-nicotinamide and (b) nicotinamide in the plasma of male rats following a single IV administration of 4,6-d2-nicotinamide at nominal dose levels of 20 mg/kg (Image 9), 60 mg/kg (Image 10) and 120 mg/kg (Image 11). Endogenous NA is released after intravenous administration of d2-NA.Unlabelled Image