TABLE 2.
Pharmacokinetic/metric parameters determined by non-compartmental analysis following a single oral dose of SAR405838 (25 mg/kg) in wild-type, Mdr1a/b–/–, Bcrp1–/–, and Mdr1a/b–/–Bcrp1–/– FVB mice
Values are means ± SE.
| Plasma | Brain | |||||||
|---|---|---|---|---|---|---|---|---|
| Wild Type | Mdr1a/b−/− | Bcrp1−/− | Mdr1a/b−/− Bcrp1−/− | Wild Type | Mdr1a/b−/− | Bcrp1−/− | Mdr1a/b−/− Bcrp1−/− | |
| t1/2 (hour) | 3.26 | 4.18 | 3.02 | 5.08 | 4.03 | 10.1 | 3.36 | 12.1 |
| Tmax (hour) | 8 | 8 | 4 | 2 | 8 | 16 | 4 | 8 |
| Cmax (ng/ml) | 4651 | 3582 | 7209 | 6164 | 161 | 4176 | 159 | 4554 |
| AUC0→tlast [(h*ng)/ml] | 60,425 ± 3584 | 40,490 ± 2559 | 68,107 ± 9193 | 62,490 ± 7253 | 1995 ± 132 | 74,213 ± 5908 | 1925 ± 249 | 75,281 ± 9392 |
| AUC0→∞ [(h*ng)/ml] | 61,195 | 41,382 | 68,681 | 65,867 | 1335 | 97,283 | 1956 | 100,663 |
| F oral | 0.732 | NA | NA | 0.809 | — | — | — | — |
| Vd/F (ml/kg) | 1922 | 3642 | 1585 | 2778 | — | — | — | — |
| CL/F (ml/kg) | 409 | 604 | 364 | 379 | — | — | — | — |
| Kpbrain | — | — | — | — | 0.0218 | 2.35 | 0.0285 | 1.53 |
| DA | — | — | — | — | 1 | 108 | 1.31 | 70.1 |
AUC0-tlast, area under the curve from zero to the time of last measured concentration; AUC0–∞, area under the curve from zero to time infinity; CL/F, apparent clearance; Cmax, observed maximum concentration; DA, distribution advantage, the ratio of Kpknockout to Kpwild-type; F, absolute bioavailability, ratio of the dose corrected AUC(0–∞) following oral administration to dose corrected AUC(0–∞) following intravenous administration; Kpbrain (AUC ratio), the ratio of AUC(0–∞,brain) to AUC(0–∞,plasma) using total drug concentrations; Tmax, time to reach the maximum concentration; Vd/F, apparent volume of distribution.