Pharmacokinetic parameters for NVS-CRF38 and [13CD3] NVS-CRF38 in male Sprague-Dawley rats after intravenous and oral administration
For intravenous administration, the compounds were formulated in 50:50 (v/v) PEG200:saline; the dose volume was 1 ml/kg. For oral administration, compounds were formulated as a suspension in 0.5% methylcellulose containing 0.5% Tween 80 and dosed at 5 ml/kg. Data are the mean and S.D. of four rats.
| Parameters | NVS-CRF38 | [13CD3] NVS-CRF38 | ||
|---|---|---|---|---|
| Parent | Metabolite | Parent | Metabolite | |
| Intravenous | ||||
| Dose (mg/kg) | 1 | − | 1 | − |
| Cmax (nM) | − | 74 ± 20 | − | 9 ± 1** |
| Tmax (h) | − | 0.8 ± 0.0 | − | 0.6 ± 0.3 |
| AUC0→∞ (nM⋅h) | 2255 ± 211 | 402 ± 157 | 4853 ± 327** | 130 ± 69 |
| CLb (ml/min/kg) | 21.2 ± 2.0 | − | 9.7 ± 0.7** | − |
| Vss (l/kg) | 3.3 ± 0.7 | − | 3.8 ± 0.6 | − |
| Half-life (h) | 2.7 ± 0.7 | 6.9 ± 1.8 | 5.2 ± 1.4 | 12.8 ± 7.5 |
| MRT (h) | 2.6 ± 0.3 | − | 6.5 ± 1.5* | − |
| fm | 0.21 ± 0.08 | 0.07 ± 0.04 | ||
| Oral | ||||
| Dose (mg/kg) | 10 | − | 10 | − |
| Cmax (nM) | 4111 ± 265 | 674 ± 171 | 6148 ± 1506 | 113 ± 20 |
| Tmax (h) | 0.8 ± 0.0 | 0.6 ± 0.3 | 1.3 ± 1.0 | 1.0 ± 0.4 |
| AUC0→∞ (nM⋅h) | 23,391 ± 1475 | 4554 ± 1510 | 60,218 ± 14,726* | 1812 ± 631** |
| Oral half-life (h) | 3.5 ± 0.6 | 9.3 ± 2.2 | 5.6 ± 1.1* | 14.6 ± 6.0 |
| F (%) | 104 ± 7 | − | 124 ± 30 | − |
| Blood distribution | ||||
| fub | 0.17 ± 0.02 | − | 0.14 ± 0.02 | − |
| BPR | 0.83 ± 0.07 | − | 0.86 ± 0.05 | − |