Establishment of small molecule-based in silico models for prediction of hERG and Nav1.5 inhibitions for drug discovery

s / Toxicology Letters 229S (2014) S40–S252 S161 none of them can simulate the effect of chelation in lead poisoning. We aimed to adapt an existing PBPK lead model, developed by O’Flaherty, so as to describe the effect of DMSA chelation therapy on lead kinetics. Materials and methods: We developed a two-compartment kinetic model for DMSA (gut and central compartment). We fitted unknown model parameters and validated the model using data from different published studies. Subsequently, we included this DMSA model in the O’Flaherty one. The accuracy of the adapted O’Flaherty model prediction was assessed by simulating a clinical observation: a 46-year-oldmanwho took an Ayurvedic remedy for about 13weeks. The pre-chelation lead level in bloodwas 99 g/dL. The patient received two DMSA treatments (30mg/kg/day DMSA for 9 days, 12 days without treatment, then 30mg/kg/day DMSA for 5 days). Results: The post-chelation lead blood concentrations predicted by the adapted O’Flaherty model were 46 g/dL and 36.5 g/dL versus 44 g/dL and 31 g/dLmeasured, respectively, after the two chelation treatments. Conclusion: This adapted O’Flahertymodel might be suitable for predicting the effect of DMSA therapy on lead kinetics. However, themodel needs further validationwith other lead poisoning cases. http://dx.doi.org/10.1016/j.toxlet.2014.06.553