Background: CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was\r\nshown to be 50ââ?¬â??100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the\r\npresent investigation, we have established an analytical method for the quantification of CR8 in biological samples\r\nand evaluated its bioavailability, biodistribution and pharmacokinetics in mice.\r\nMethods: A liquid chromatography method utilizing UV-detection was used for the determination of CR8. CR8 was\r\nadministered either orally (100 mg/kg) or i.v. (50 mg/kg) and the animals were sacrificed at different time points.\r\nBlood samples and organs were collected, after which the pharmacokinetic parameters were calculated for plasma\r\nand organs.\r\nResults: CR8 was eluted at 5 minutes in the high performance liquid chromatography system used. The LLOQ\r\ndetection was 0.10 Ã?µg/ml and linearity was observed within the 0.10-10 Ã?µg/ml range (r2 > 0.998). The accuracy and\r\nprecision were >86%, while the recovery from plasma was >95%. CR8 was stable for 2 months at room\r\ntemperature in both solution and plasma. CR8 pharmacokinetics was fitted to a two-compartment open model\r\nafter oral administration and to a one compartment model after i.v. injection. The elimination half-life was about\r\n3 hours. Organ exposure to CR8 (expressed as % AUC organ vs. AUC plasma) was highest in liver (205%), adipose\r\ntissue (188%) and kidney (150%) and low in bone marrow (30%) and brain (15%) as compared to plasma. The oral\r\nbioavailability of CR8 was found to be essentially 100%.\r\nConclusions: We have developed a rapid and simple method for the analysis of CR8. CR8 pharmacokinetics pattern\r\nshowed 100% bioavailability, long half-life and limited distribution to brain and bone marrow, which may allow\r\nsystemic exposure higher than the IC50 reported for cell death in tumor cell lines. CR8 displays favorable pharmacological\r\nproperties and is therefore a good candidate for future clinical studies.
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