title: Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat.
abstract: The pharmacokinetics, biodistribution and the metabolic pathway of roscovitine were investigated in Sprague-Dawley rats after a single intravenous dose of 25 mg/kg. Blood, lungs, kidney, liver, testis, adipose tissue, spleen and brain were removed at different time-points. Plasma and tissue samples were analyzed using high performance liquid chromatography. The metabolites were identified using liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance spectroscopy. Roscovitine (MW=354) was cleared rapidly from circulation and highly distributed to the tissues. The elimination half-life of roscovitine in plasma and tissues was short (<30 min). A major metabolite (M1) was observed mainly in plasma and in lower levels in all other tissues. M1 was identified as conversion of the hydroxyl-group at C2 to carboxylic acid (MW=368). A second metabolite (M2) was observed mainly in liver and kidney and identified as a hydroxylation product of the C8 of the purine-ring (MW=370). A third metabolite (M3) was found in several organs and corresponded to N-dealkylation of the N9-isopropyl side-chain (MW=312). Roscovitine concentrations in the brain were 30% of that observed in plasma, however no metabolites were detected in brain. In this investigation, three major metabolites of roscovitine were isolated and identified. Also, it was shown that roscovitine eliminates rapidly from both blood and tissues.
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska Institute, Sweden.
authors.forename: Marina
authors.initials: M
authors.lastname: Vita
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Rehim
authors.forename: Susanne
authors.initials: S
authors.lastname: Olofsson
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hassan
authors.forename: Lennart
authors.initials: L
authors.lastname: Meurling
authors.forename: Ake
authors.initials: A
authors.lastname: Sidén
authors.forename: Mabel
authors.initials: M
authors.lastname: Sidén
authors.forename: Tommy
authors.initials: T
authors.lastname: Pettersson
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011687:Purines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D014018:Tissue Distribution
chemical_list: D011687:Purines; D000077546:Roscovitine