Abstract
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 (Kpuu,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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder, which leads to an impairment of many cognitive functions, the short-term memory[1]
SLOH were observed in plasma, microsomes and deactivated hepatocytes of all species for more than 4 hours at 37 °C (half-life elimination (t1/2) > 24 h)
We have demonstrated that SLOH and SLM were affected by the efflux transporters (P-gp and BCRP) in Caco-2 cell study and uptake transporter (OATP2B1) in stably transfected HEK293 cells study (Fig. 2)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder, which leads to an impairment of many cognitive functions, the short-term memory[1]. A series of carbazole-based cyanine compounds with various functionalized pyridinium or quinolinium moieties has been reported to inhibit the Aβ aggregation[7]. PK usually describes the drug concentration-time courses in body fluids after administration. Establishment of PK-PD models is to evaluate dose-concentration-response relationships and subsequently describe and predict the effect-time courses. The compound-target/system interactions, such as signal transduction, tolerance and slow receptor-binding, can be systemically studied by mechanistic processes, incorporated into PK/PD-modelling, which are essential in efficacy and safety prediction[11]. This work elucidated the systemic clearance (hepatic, renal and biliary clearance) and brain penetration (transporters and exposure) mechanism of abovementioned carbazole-based cyanine compounds in liver microsomes, hepatocytes, Caco-2 cell, OATP1B1/1B3/2B1/1A2 stably transfected HEK293 cell and in vivo animal models
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