| Autor: |
Ito, Ryo, Morio, Hanae, Baba, Tomoyo, Sakaguchi, Yasuyuki, Wakayama, Naomi, Isogai, Ryuto, Yamaura, Yoshiyuki, Komori, Takafumi, Furihata, Tomomi |
| Předmět: |
|
| Zdroj: |
Pharmaceutical Research; Jul2022, Vol. 39 Issue 7, p1575-1586, 12p |
| Abstrakt: |
Purpose: In vitro human blood–brain barrier (BBB) models in combination with central nervous system-physiologically based pharmacokinetic (CNS-PBPK) modeling, hereafter referred to as the "BBB/PBPK" method, are expected to contribute to prediction of brain drug concentration profiles in humans. As part of our ongoing effort to develop a BBB/PBPK method, we tried to clarify the relationship of in vivo BBB permeability data to those in vitro obtained from a human immortalized cell-based tri-culture BBB model (hiBBB), which we have recently created. Methods: The hiBBB models were developed and functionally characterized as previously described. The in vitro BBB permeabilities (Pe, × 10–6 cm/s) of seventeen compounds were determined by permeability assays, and in vivo BBB permeabilities (QECF) for eight drugs were estimated by CNS-PBPK modeling. The correlation of the Pe values with the QECF values was analyzed by linear regression analysis. Results: The hiBBB models showed intercellular barrier properties and several BBB transporter functions, which were enough to provide a wide dynamic range of Pe values from 5.7 ± 0.7 (rhodamine 123) to 2580.4 ± 781.9 (rivastigmine). Furthermore, the in vitro Pe values of the eight drugs showed a good correlation (R2 = 0.96) with their in vivo QECF values estimated from human clinical data. Conclusion: We show that in vitro human BBB models provide clinically relevant BBB permeability that can be used as input for CNS-PBPK modeling. Therefore, our findings will encourage the development of a BBB/PBPK method as a promising approach for predicting brain drug concentration profiles in humans. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
Full text from SpringerLink