ABSTRACT
PURPOSE: The aim of this study was to evaluate the oral exposure predictions obtained early in drug discovery with a generic GastroPlus Advanced Compartmental And Transit (ACAT) model based on the in vivo intravenous blood concentration-time profile, in silico properties (lipophilicity, pKa) and in vitro high-throughput absorption-distribution-metabolism-excretion (ADME) data (as determined by PAMPA, solubility, liver microsomal stability assays). METHODS: The model was applied to a total of 623 discovery molecules and their oral exposure was predicted in rats and/or dogs. The predictions of Cmax, AUClast and Tmax were compared against the observations. RESULTS: The generic model proved to make predictions of oral Cmax, AUClast and Tmax within 3-fold of the observations for rats in respectively 65%, 68% and 57% of the 537 cases. For dogs, it was respectively 77%, 79% and 85% of the 124 cases. Statistically, the model was most successful at predicting oral exposure of Biopharmaceutical Classification System (BCS) class 1 compounds compared to classes 2 and 3, and was worst at predicting class 4 compounds oral exposure. CONCLUSION: The generic GastroPlus ACAT model provided reasonable predictions especially for BCS class 1 compounds. For compounds of other classes, the model may be refined by obtaining more information on solubility and permeability in secondary assays. This increases confidence that such a model can be used in discovery projects to understand the parameters limiting absorption and extrapolate predictions across species. Also, when predictions disagree with the observations, the model can be updated to test hypotheses and understand oral absorption.
Subject(s)
Drug Discovery/methods , Pharmaceutical Preparations/metabolism , Animals , Computer Simulation , Dogs , Humans , Intestinal Absorption/physiology , Male , Models, Biological , Permeability , Rats , Rats, Sprague-Dawley , SolubilityABSTRACT
Pesticide smoke generating products are widely used by amateurs and professionals but there is little published information available about their burn and deposition characteristics to enable the risks associated with using these devices to be assessed. This paper investigates their burn characteristics, deposition patterns, pesticide air concentrations and potential exposure to operators. Thirteen firings were carried out in different spaces with different ventilation conditions. Three types of devices were investigated: dicloran, permethrin and red dye. Pesticide air concentrations increased after firing, reaching a maximum determined by the room volume in approximately 10 min and decreasing exponentially as a result of ventilation and deposition. Ejected pesticide was present in the aerosol phase but there were only occasional traces of vapour. Settlement of pesticide was affected by surface orientation, height, sampling material and the pesticide-to-space volume ratio. The manufacturer's recommended treatment period for dicloran of 4 h followed by half an hour of ventilation may be insufficient to reduce pesticide to safe levels for re-entry under very calm conditions.
