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 100 ng/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 750 ng/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 (25 mg/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 26 min, respectively). The distribution volume was determined to 3.5 l/kg and the clearance (Cl) was 29.5 ml/min.