Session Speaker

Pharmacokinetics and biodistribution of Cdk inhibitors as anticancer drugs
Moustapha Hassan, Hatem Sallam Laurent Meijer, Zuzana Hassan
Sweden

Cyclin-dependent kinases (Cdks) and their regulators have frequently abnormal behavior in tumors. Low molecular weight pharmacological inhibitors of Cdks including (R)-roscovitine and olomoucin are currently in clinical trials for the treatment of several tumor diseases. Later, a bioisoster (N-&-N1) of roscovitine with 2-3 fold enhanced potency as anti-tumoral drug was introduced. N-&-N1 shows exquisite selectivity for CDKs, compared to (R)-roscovitine. Recently, the second generation of Cdk inhibitors was introduced including CR8; that was shown to be 50-100-fold more potent than roscovitine in inducing apoptosis in different tumor cell lines.

Generally, the first generation of Cdk inhibitors showed poor pharmacokinetic profiles i.e. short elimination half-life and high clearance that might explain the low efficacy observed against tumors in vivo. Moreover, the pharmacokinetics and biodistribution of roscovitine was both age and time-schedule dependent. The distribution of roscovitine over blood-brain barrier was significantly higher in young rats compared to adults which might benefit it use for the treatment of brain tumors. On the other hand, CR8 showed high bioavailability and favorable biodistribution and pharmacokinetics in mice. All together show the importance of early pharmacokinetic, biodistribution and metabolic studies in drug discovery for successful drug candidate.