title: ADME studies of [5-(3)H]-2'-O-methyluridine nucleoside in mice: a building block in siRNA therapeutics.
abstract: The chemical modification 2'-O-methyl of nucleosides is often used to increase siRNA stability towards nuclease activities. However, the metabolic fate of modified nucleosides remains unclear. Therefore, the aim of this study was to determine the mass balance, pharmacokinetic, and absorption, distribution, metabolism, and excretion (ADME)-properties of tritium-labeled 2'-O-methyluridine, following a single intravenous dose to male CD-1 mice. The single intravenous administration of [5-(3)H]-2'-O-methyluridine was well tolerated in mice. Radioactivity was rapidly and widely distributed throughout the body and remained detectable in all tissues investigated throughout the observation period of 48 h. After an initial rapid decline, blood concentrations of total radiolabeled components declined at a much slower rate. [(3)H]-2'-O-Methyluridine represented a minor component of the radioactivity in plasma (5.89% of [(3)H]-AUC 0-48 h). Three [(3)H]-2'-O-methyluridine metabolites namely uridine (M1), cytidine (M2), and uracil (M3) were the major circulating components representing 32.8%, 8.11%, and 23.6% of radioactivity area under the curve, respectively. The highest concentrations of total radiolabeled components and exposures were observed in kidney, spleen, pineal body, and lymph nodes. The mass balance, which is the sum of external recovery of radioactivity in excreta and remaining radioactivity in carcass and cage wash, was complete. Renal excretion accounted for about 52.7% of the dose with direct renal excretion of the parent in combination with metabolism to the endogenous compounds cytidine, uracil, cytosine, and cytidine.
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lozac'h
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Jesper
authors.initials: J
authors.lastname: Christensen
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Faller
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: van de Kerkhof
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Joel
authors.initials: J
authors.lastname: Krauser
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Maxime
authors.initials: M
authors.lastname: Garnier
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Litherland
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Catoire
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Natt
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Jurg
authors.initials: J
authors.lastname: Hunziker
authors.affiliation: Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics Novartis Pharma AG Fabrikstrasse 14, 1.17 CH-4002 Basel Switzerland.
authors.forename: Piet
authors.initials: P
authors.lastname: Swart
keywords: 2′‐O‐methyluridine; ADME; QWBA; SiRNA; lithium adducts formation; mass spectrometry