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

TY - JOUR

T1 - Pharmacokinetics of the SABRE agent 4,6-d2-Nicotinamide and also Nicotinamide in rats following oral and intravenous administration

AU - Linnik, Inna

AU - Rayner, Peter John

AU - Stow, Ruth

AU - Duckett, Simon

AU - Cheetham, Graham Mark Thomas

N1 - Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - To prepare the way for using the isotopically labelled SABRE hyperpolarised 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 hours 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.

AB - To prepare the way for using the isotopically labelled SABRE hyperpolarised 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 hours 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.

KW - SABRE, Hyperpolarisation, Deuteration, Pharmacokinetics, Nicotinamide

KW - SABRE

KW - Nicotinamide

KW - Deuteration

KW - Pharmacokinetics

KW - Hyperpolarization

UR - http://www.scopus.com/inward/record.url?scp=85065562027&partnerID=8YFLogxK

U2 - 10.1016/j.ejps.2019.05.004

DO - 10.1016/j.ejps.2019.05.004

M3 - Article

SN - 0928-0987

VL - 135

SP - 32

EP - 37

JO - European journal of pharmaceutical sciences

JF - European journal of pharmaceutical sciences

M1 - EJPS-D-19-00374R1

ER -