TABLE 3.
Free fraction (fu) values, partition coefficient of brain (Kpbrain and Kpuu, brain), and distribution advantage
Data presented as mean ± S.D.
| Intravenous | Oral | |||||
|---|---|---|---|---|---|---|
| Wild Type | Mdr1a/1b−/− Bcrp1−/− | Wild Type | Mdr1a/1b−/− | Bcrp1−/− | Mdr1a/1b−/− Bcrp1−/− | |
| Kpbrain | 0.0275 | 1.29 | 0.0218 | 2.35 | 0.0285 | 1.53 |
| fu, plasma | 0.00059 ± 0.00034 | |||||
| fu, brain | 0.00015 ± 0.000035 | |||||
| Kpuu, brain | 0.007 | 0.328 | 0.006 | 0.598 | 0.007 | 0.389 |
| DAtotal | 1 | 46.8 | 1 | 108 | 1.31 | 70.1 |
DA, distribution advantage, the ratio of Kpknockout to Kpwild-type; fu,brain, free fraction of SAR405838 in brain homogenate determined by rapid equilibrium dialysis (N = 9); fu,plasma, free fraction of SAR405038 in plasma determined by rapid equilibrium dialysis (N = 9); Kp (AUC ratio), the ratio of AUC(0–∞,brain) to AUC(0–∞,plasma) using total drug concentrations; Kpuu (AUC ratio), the ratio of AUC(0–∞,brain) to AUC(0–∞,plasma) using free drug concentrations.