Conversion of I to II in plasma of rats dosed i.v. with Compound I or II
| Dose | i.v. Dose of Compound I (mw 1004.9 salt) | ||
|---|---|---|---|
| 1 | 8 | 25 | |
| mg/kg | |||
| Dose (μmol/kg) | 1.00 | 7.96 | 24.88 |
| AUC of II (ng·h/ml) | 568 ± 121 | 6249 ± 1373 | 22392 ± 1158 |
| Exposure of II (%)1-a | ∼91% | ∼100% | NC1-b |
| Dose | i.v. Dose of Compound II (mw 534.4 free base) | ||
|---|---|---|---|
| 0.2 | 2 | 5 | |
| mg/kg | |||
| Dose (μmol/kg) | 0.37 | 3.74 | 9.36 |
| AUC of II (ng·h/ml) | 201 ± 52 | 2658 ± 335 | 6377 ± 1242 |
| Clearance (ml/min/kg) | 17.6 ± 5.3 | 12.7 ± 1.7 | 13.4 ± 2.6 |
| V d ss (liters/kg) | 3.2 ± 0.5 | 2.8 ± 0.1 | 2.5 ± 0.2 |
| T 1/2 1-c (h) | 2.7 ± 0.4 | 3.2 ± 0.4 | 2.4 ± 0.4 |
↵1-a Exposure of II was estimated by comparing the AUC values of II in plasma after dosing of I with that after dosing of II to rats. At 1 mg/kg, the relative exposure was calculated from the 0.2 and 2 mg/kg i.v. doses of II. At 8 mg/kg, the relative exposure was calculated from the 2 and 5 mg/kg i.v. doses of II. Calculations were normalized for dose.
↵1-b NC: not calculated.
↵1-c For T1/2 calculations, the terminal rate constant was estimated by linear regression of the last three to four data points: 6 to 24 h for 5 mg/kg, 6 to 10 h for 0.2 mg/kg, and 6 to 24 h for 2 mg/kg.