PURPOSE: To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane). METHODS: Three PAMPA (BD pre-coated and PBLE with 2 different lipid volumes) models were tested with 108 drugs. Abraham solvation descriptors were used to interpret the in vitro-in vivo correlation with 282 in situ brain perfusion measurements, spanning over 5 orders of magnitude. An in combo PAMPA model was developed from combining measured PAMPA permeability with one H-bond descriptor. RESULTS: The in combo PAMPA predicted 93% of the variance of 197 largely efflux-inhibited in situ permeability training set. The model was cross-validated by the "leave-many-out" procedure, with q(2) = 0.92 ± 0.03. The PAMPA models indicated the presence of paramembrane water channels. Only the PBLE-based PAMPA-BBB model with sufficient lipid to fill all the internal pore space of the filter showed a wide dynamic range window, selectivity coefficient near 1, and was suitable for predicting BBB permeability. CONCLUSION: BBB permeability can be predicted by in combo PAMPA. Its speed and substantially lower cost, compared to in vivo measurements, make it an attractive first-pass screening method for BBB passive permeability.
PURPOSE: To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane). METHODS: Three PAMPA (BD pre-coated and PBLE with 2 different lipid volumes) models were tested with 108 drugs. Abraham solvation descriptors were used to interpret the in vitro-in vivo correlation with 282 in situ brain perfusion measurements, spanning over 5 orders of magnitude. An in combo PAMPA model was developed from combining measured PAMPA permeability with one H-bond descriptor. RESULTS: The in combo PAMPA predicted 93% of the variance of 197 largely efflux-inhibited in situ permeability training set. The model was cross-validated by the "leave-many-out" procedure, with q(2) = 0.92 ± 0.03. The PAMPA models indicated the presence of paramembrane water channels. Only the PBLE-based PAMPA-BBB model with sufficient lipid to fill all the internal pore space of the filter showed a wide dynamic range window, selectivity coefficient near 1, and was suitable for predicting BBB permeability. CONCLUSION:BBB permeability can be predicted by in combo PAMPA. Its speed and substantially lower cost, compared to in vivo measurements, make it an attractive first-pass screening method for BBB passive permeability.
Authors: Timothy S Carpenter; Daniel A Kirshner; Edmond Y Lau; Sergio E Wong; Jerome P Nilmeier; Felice C Lightstone Journal: Biophys J Date: 2014-08-05 Impact factor: 4.033
Authors: José David Sánchez-Martínez; Alberto Valdés; Rocio Gallego; Zully Jimena Suárez-Montenegro; Marina Alarcón; Elena Ibañez; Gerardo Alvarez-Rivera; Alejandro Cifuentes Journal: Front Nutr Date: 2022-06-16