title: Age-dependent pharmacokinetics and effect of roscovitine on Cdk5 and Erk1/2 in the rat brain.
abstract: Roscovitine is a cyclin-dependent kinase (Cdk) and signal-regulated kinase (Erk1/2) inhibitor that has been shown to be effective against several cancer types including brain tumors. We have shown previously that roscovitine crosses the blood brain barrier (BBB) and is rapidly eliminated from both plasma and brain in adult rats. However, age-dependent kinetics and its effects on the brain have not been reported. In the present study, we investigated the pharmacokinetics of roscovitine in adult and in 14 days old rats after the administration of a single dose of 25 mg/kg. Moreover, we studied the effect of the drug on Cdk5 and Erk1/2 activities in three brain regions, hippocampus, frontal cortex and cerebellum. The pharmacokinetics of roscovitine followed a two-compartment model in both plasma and brain in both adult and young rats. The terminal elimination half-life was 7 h in brain as well as in plasma in rat pups compared to < 0.5 h observed in adult rats. Brain exposure expressed as AUC brain/AUC plasma was 100% in rat pups compared to 20% found in adult rats. Roscovitine induced a significant Cdk5 inhibition and significant Erk1/2 activation in all studied pups brain regions at 2 h. This is the first study describing age-dependent pharmacokinetics of roscovitine and showing the high brain exposure of infant rats to the drug. Thus, roscovitine may be a promising candidate for the treatment of brain tumors in children.
authors.affiliation: Experimental Cancer Medicine, Clinical Research Centre, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden.
authors.forename: Hatem
authors.initials: H
authors.lastname: Sallam
authors.forename: Patricia
authors.initials: P
authors.lastname: Jimenez
authors.forename: Hairong
authors.initials: H
authors.lastname: Song
authors.forename: Marina
authors.initials: M
authors.lastname: Vita
authors.forename: Angel
authors.initials: A
authors.lastname: Cedazo-Minguez
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001921:Brain / Q000201:enzymology*; D002531:Cerebellum / Q000201:enzymology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology; D006207:Half-Life; D006624:Hippocampus / Q000201:enzymology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011687:Purines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D000077546:Roscovitine; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; D048049:Extracellular Signal-Regulated MAP Kinases