Prediction of Human Brain Penetration of P-glycoprotein and Breast Cancer Resistance Protein Substrates Using In Vitro Transporter Studies and Animal Models.

Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro-in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (C _b,u ), unbound plasma (C _p,u ), and CSF compound concentrations (C _CSF ) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (C _b,u /C _p,u and C _CSF /C _p,u ) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although C _CSF does not quantitatively correspond to C _b,u for efflux transporter substrates, it is mostly within 3-fold higher of C _b,u in rat and NHP, suggesting that C _CSF can be used as a surrogate for C _b,u . Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates.
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