Systemic clearance and brain distribution of carbazole-based cyanine compounds as Alzheimer’s disease drug candidates

摘要

SLM and SLOH, two analogues of carbazole-based cyanine compounds, have been shown to inhibit β-amyloid peptide aggregation in vitro and in Alzheimer’s disease model mice, which could be potentially developed into drugs for disease treatment. To pave the way for further pharmacokinetics-pharmacodynamics study, we set to investigate these compounds’ systemic clearance pathways and their brain exposure. We found that they generally exhibited relatively low plasma clearance which comprised of hepatic clearance and biliary clearance. Phase I oxidative metabolites for SLM and for SLOH upon microsomes incubation were identified, and the metabolism by CYP3A4 were found to be the major (>70%) hepatic clearance pathway, while the efflux by P-gp and BCRP located in the canalicular membrane of hepatocytes led to high biliary clearance. The permeation of SLM and SLOH through the brain endothelium was affected by the efflux transporters (P-gp and BCRP) and influx transporter (OATP2B1). The unbound interstitial fluid to plasma ratio (K puu,brain) was 8.10 for SLOH and 11.0 for SLM, which favored brain entry and were several folds higher than that in wild-type mice. Taken together, these carbazole compounds displayed low plasma clearance and high brain permeability, which entitle further development.