Evaluation of Human Liver Microtissues for Drug Screening on Schistosomula.

Schistosomiasis is a major neglected tropical disease with more than 200 million infections annually. Despite only one drug, praziquantel, being available, the drug pipeline against schistosomiasis is empty, and drug screening tools have limitations. We evaluated the potential of human liver microtissues (hLiMTs) in antischistosomal drug discovery. Because hLiMTs express all human P450 enzymes, they are an excellent tool to evaluate compounds' bioinactivation, bioactivation, and toxicity. To validate the metabolic conversion capacity of hLiMTs, we first quantified ()- and ()-praziquantel and the main metabolite -OH-praziquantel following incubation with 0.032-50 μM (0.01-15.62 μg/mL) praziquantel for up to 72 h by a validated LC-MS/MS method. We cocultured hLiMTs with newly transformed schistosomula (NTS) and evaluated the antischistosomal activity and cytotoxicity of three prodrugs terfenadine, tamoxifen citrate, and flutamide. HLiMTs converted 300-350 ng ()-praziquantel within 24 h into -OH-praziquantel. We observed changes in the IC values for terfenadine, flutamide, and tamoxifen citrate in comparison to the standard NTS assay Cytotoxicity was observed at high concentrations of flutamide and tamoxifen citrate. An platform containing hLiMTs could serve as an advanced drug screening tool for , providing information on reduced or increased activity and toxicity.