Back to Search
Start Over
Evaluation of the reliability and applicability of human unbound brain-to-plasma concentration ratios
- Publication Year :
- 2022
- Publisher :
- Cold Spring Harbor Laboratory, 2022.
-
Abstract
- BackgroundBlood-brain barrier permeability (BBB Pe) and unbound brain-to-plasma concentration ratio (Kp,uu,brain) are relevant parameters describing the brain uptake potential of compounds. BBB efflux by transporter proteins, mainly MDR-1 and BCRP, is an essential factor determining Kp,uu,brain. Kp,uu,brain-values are commonly estimatedin vivoin rats and monkeys and predicted usingin silicomethodology. Such estimates can be used to predict corresponding human clinical values.ObjectiveThe objective of the study was to evaluate the reliability and applicability of human clinical Kp,uu,brain-data for understanding and predictions of brain uptake in man.MethodologyKp,uu,brainin rats, monkeys and humans, measured andin silicopredicted MDR-1 and BCRP substrate specificities andin silicopredicted passive Pewere used for the analysis.In silicopredictions were done using the ANDROMEDA by Prosilico ADME/PK-prediction software.Results and DiscussionRat and monkey Kp,uu,brain-values were highly correlated (R^2=0.74; n=17). Based on this finding a correlation between rat and human Kp,uu,brainwas expected. However, no correlation between rat and human Kp,uu,brainwas found (R^2=0.01; n=13). There was no (as also anticipated) correlation between passive Peand human Kp,uu,brain(R^2=0.04; n=16) and compounds with measured or predicted efflux did not have lower Kp,uu,brainthan compounds without efflux. The compound with highest Kp,uu,brainin man (2.8) is effluxed and predicted to have high passive Peand has no apparent efflux at the rat BBB. The MDR-1 substrate with highest Kp,uu,brainin rat (2.4) has very low Kp,uu,brainin man (0.15) is predicted to have high passive Pe.ConclusionResults indicate that available human Kp,uu,brain-data are too uncertain to be applicable for validation of predictions and understanding of clinical brain uptake of drugs and drug candidates.
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........2e837fad30f62592a1e6e99f392081f5
- Full Text :
- https://doi.org/10.1101/2022.11.14.516429