P-glycoprotein deficient mouse in situ blood–brain barrier permeability and its prediction using an in combo PAMPA model

Abstract

The purpose of the study was to assess the permeability of mouse blood-brain barrier (BBB) to a diverse set of compounds in the absence of P-glycoprotein (Pgp) mediated efflux, to predict it using an in combo PAMPA model, and to explore its role in brain penetration classification (BPC). The initial brain uptake (K in ) of 19 compounds in both wild-type and Pgp mutant [mdr1a(−/−)] CF-1 mice was determined by the in situ brain perfusion technique. PAMPA measurements were performed, and the values were used to develop an in combo model, including Abraham descriptors. Published rodent K in values were used to enhance the dataset and validate the model. The model predicted 92% of the variance of the training set permeability. In all, 182 K in values were considered in this study, spanning four log orders of magnitude and where Pgp decreased brain uptake by as much as 14-fold. The calculated permeability-surface area (PS) values along with literature reported brain tissue binding were used to group molecules in terms of their brain penetration classification. The in situ BBB permeability can be predicted by the in combo PAMPA model to a satisfactory degree, and can be used as a lower-cost, high throughput first-pass screening method for BBB passive permeability.

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

“…Ignoring this [49,50], the logS-pH data above pH 7 might suggest that the pK a of haloperidol at 37 °C is 8.0. This would not be in agreement with the pK a 8.29 independently determined at 37 °C [60] and 8.60 at 25 °C [61]. Based solely on the solubility measurements, none of the three possibilities can be definitively ruled out, and additional investigation might be desirable.…”

The Grasshopper: A Novel Model for Assessing Vertebrate Brain Uptake

“…However, as seen in Fig. 4A, no correlation is found between the in situ data extracted from Dagenais et al (2009) and the MDCK-MDR1 data extracted from the work of Di et al (2009) or generated in this study. As shown by Di et al, the MDCK-MDR1 data do not correlate with in situ perfusion data, and a number of compounds are detected as false positives and even more problematic false negatives (i.e., CNS drugs that are low or nonpermeating in the MDCK-MDR1 assay).…”

“…4. Correlations between LogPS extracted from Dagenais et al (2009) and the different permeability models used in this work: apparent permeability measured using MDCK-MDR1 cells (A), logarithm of grasshopper brain concentration obtained after using 10 mM exposure concentration (B), logarithm of grasshopper brain concentration obtained after using 3 mM exposure concentration (C), logarithm of grasshopper brain concentration obtained after 3 mM exposure concentration + verapamil (D). Only compounds known not to be Pgp substrates are included in (B).…”

ANG4043, a Novel Brain-Penetrant Peptide–mAb Conjugate, Is Efficacious against HER2-Positive Intracranial Tumors in Mice

“…4A). Using the same species and method, Dagenais and colleagues reported K in values for a variety of compounds (34). For comparison, the K in for the unconjugated anti-HER2 mAb is close to that of the antiviral drug ritonavir K in (3.0 Â 10 À4 mL/g/s), which is classified having low CNS penetration (35).…”