title: Analysis of roscovitine using novel high performance liquid chromatography and UV-detection method: pharmacokinetics of roscovitine in rat.
abstract: Roscovitine (2-(R)-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine, is a potent and selective inhibitor of cyclin-dependent kinases (CDKs). It inhibits cdc2, cdk2, cdk5 and erk 1 and 2 by competing for the ATP binding domain of the kinases. It inhibits cell proliferation; induces DNA fragmentation and causes cell cycle arrest in S phase. Its stability and toxicity are not fully known. A liquid chromatography method was developed to measure roscovitine in human and rat plasma. The lower limit of quantitation (LLOQ) was 100ng/ml; the intra- and inter-day precision was below 10% at all control levels. Likewise, the accuracy between and within days was lower than 6% at all levels. The drug was stable at room temperature. Twenty-four hours at room temperature has result in a decrease of only 9% of the drug. The recovery of roscovitine from plasma was 84% at 750ng/ml. The present method was used to study the pharmacokinetics of the drug in a rat model. The present investigation, to the authors' knowledge, is the first analytical method reported and the first pharmacokinetics investigation of roscovitine in rat. Roscovitine was administered as a bolus injection (25mg/kg body weight). The pharmacokinetic analysis showed that roscovitine is fitted to a two-compartment open-mode with a biphasic elimination half-life (6 and 26min, respectively). The distribution volume was determined to 3.5l/kg and the clearance (Cl) was 29.5ml/min.
authors.affiliation: Department of Neurology, R-54, Huddinge University Hospital, Karolinska Institute, S-141 86 Stockholm, Sweden. moustapha.hassan@medhs.ki.se
authors.forename: Marina
authors.initials: M
authors.lastname: Vita
authors.forename: Lennart
authors.initials: L
authors.lastname: Meurling
authors.forename: Tommy
authors.initials: T
authors.lastname: Pettersson
authors.forename: Mabel
authors.initials: M
authors.lastname: Cruz-Sidén
authors.forename: Ake
authors.initials: A
authors.lastname: Sidén
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006801:Humans; D011687:Purines / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D013056:Spectrophotometry, Ultraviolet / Q000379:methods
chemical_list: D011687:Purines; D000077546:Roscovitine