Abstract:
The available therapeutic options for hepatocellular carcinoma (HCC) are quite limited and rapidly exhausted e.g., to acquired resistance. This explains the urgent need for new therapeutic approaches. In the mouse model, it was possible to overcome resistance to the multikinase inhibitor Sorafenib (SRF) by inhibiting p38α-mitogen-activated protein kinase (MAPK). As Skepinone L (SKL) is a highly potent inhibitor of p38α MAPK with outstanding selectivity, a combined therapy of SKL with SRF represents a promising approach to HCC therapy. Poor pharmacokinetic properties are one of the main reasons for the termination of clinical trials prior to market approval. The failure of a new therapy during the clinical trial causes very high costs and loss of time. To mitigate this risk, a comprehensive elucidation of the pharmacokinetic profile of SKL in different preclinical animal species was performed in this thesis. Despite distinct species-specific differences, most of the obtained parameters show that SKL exhibits very favourable pharmacokinetic properties in vivo. Co-administration with SRF resulted in increased plasma levels with improved absorption and elimination profiles. In contrast, SRF exposure appeared to be reduced in the presence of SKL. Incubated with human microsomes, SKL is metabolically degraded especially by conjugation with glucuronic acid. The three formed reaction products were identified as primary oxygen-bound (pO), secondary oxygen-bound (sO) and nitrogen-bound (N) glucuronide and the responsible enzymes determined. Interestingly, N-glucuronide formation was not observed in any animal species. Co incubation with SRF results in a concentration-dependent decrease in the formation of pO- and sO glucuronide. In contrast, the formation of N glucuronide seems to be induced by SRF. Metabolically unchanged SKL is mainly excreted via faeces while the glucuronides presumably leave the organism by renal elimination. Regarding the pharmacokinetics and biotransformation of SKL as well as the interaction of SKL with SRF, the obtained results in the present work show promising properties for the clinical development of the intended combinatorial therapy of HCC with both kinase inhibitors SKL and SRF.
