RESUMO
The recommended method for the biopharmaceutical evaluation of drug solubility is the shake flask; however, there are discrepancies reported about the solubility of certain compounds measured with this method, one of them is candesartan cilexetil. The present work aimed to elucidate the solubility of candesartan cilexetil by associating others assays such as stability determination, polymorphic characterization and in silico calculations of intrinsic solubility, ionized species, and electronic structures using quantum chemistry descriptors (frontier molecular orbitals and Fukui functions). For the complete biopharmaceutical classification, we also reviewed the permeability data available. The polymorphic form used was previously identified as the form I of candesartan cilexetil. The solubility was evaluated in biorelevant media in the pH range of 1.2-6.8 at 37.0°C according to the stability previously assessed. The solubility of candesartan cilexetil is pH dependent and the dose/solubility ratios obtained demonstrated the low solubility of the prodrug. The in silico calculations supported the found results and evidenced the main groups involved in the solvation, benzimidazole, and tetrazol-biphenyl. The human absolute bioavailability reported demonstrates that candesartan cilexetil has low permeability and when associated with the low solubility allows to classify it as class 4 of the Biopharmaceutics Classification System.
Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/classificação , Benzimidazóis/química , Benzimidazóis/classificação , Biofarmácia/classificação , Compostos de Bifenilo/química , Compostos de Bifenilo/classificação , Tetrazóis/química , Tetrazóis/classificação , Animais , Disponibilidade Biológica , Biofarmácia/normas , Células CACO-2 , Humanos , Permeabilidade , Pró-Fármacos/química , Pró-Fármacos/classificação , Ratos , Solubilidade , Difração de Raios X/métodosRESUMO
The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P(oct) value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).
Assuntos
Benzimidazóis/farmacocinética , Biofarmácia/métodos , Canabinoides/farmacocinética , Permeabilidade da Membrana Celular/fisiologia , Absorção Intestinal , Absorção Cutânea/fisiologia , Animais , Animais Recém-Nascidos , Benzimidazóis/classificação , Benzimidazóis/normas , Biofarmácia/normas , Canabinoides/classificação , Canabinoides/normas , Permeabilidade da Membrana Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Membranas Artificiais , Valor Preditivo dos Testes , Absorção Cutânea/efeitos dos fármacos , SuínosRESUMO
We have classified a set of 250 benzimidazoles using a criterion of structural similarity. This criterion has led us to several clusters, which keep a close relationship between the molecules belonging to each one of them and their pharmacological activity. To study the structural similarity we have built a mathematical space where chemical structures are pictured as vectors. A set of well-chosen descriptors was used as variables. These descriptors arise from graph theoretical studies and quantum mechanical calculations. Principal components analysis was employed to find the suitable dimension for the space. Finally, cluster analysis was performed to classify the set of molecules by similarity. A Euclidean metric was used as a similarity coefficient.