Table 3. Pharmacokinetics of Compounds 5, 6 and 12 in Ratsa.
| Compd | Route/Dose (mg/kg) | CLp (mL/min/kg) | Vd,ss (L/kg) | t1/2 (h) | CLrenal (mL/min/kg) | Cmax (ng/mL) | Tmax (h) | AUC0–24 (ng·h/mL) | Oral F (%) | Fa × Fgf (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| 5 | i.v./1 | 25.4 (26.0, 24.9) | 0.87 (0.74, 1.0) | 6.0 (3.4, 8.5) | 8.1 (9.7, 6.5) | – | – | 650 (634, 666) | – | – |
| p.o./10b | – | – | – | – | 358 (317, 399) | 0.25 (0.25, 0.25) | 559 (519, 598) | 8.6 (8.0, 9.2) | 12.2 (11.4, 13.2) | |
| 6 | i.v./1 | 33.1 (33, 33.2) | 1.05 (0.486, 1.62) | 5.1 (0.98, 9.1) | 4.5 (6.2, 2.8) | – | – | 502 (505, 499) | – | – |
| p.o./10b,c | – | – | – | – | 272 (236, 308) | 0.50 (0.50, 0.50) | 599 (592, 605) | 11.9 (11.8, 12.1 | 20.2 (20.0, 20.4) | |
| p.o./10b,d | – | – | – | – | 92.8 (116, 69.6) | 0.75 (0.50, 1.0) | 212e (218, 206) | 4.2 (4.3, 4.1) | 7.2 (7.3, 6.9) | |
| 12 | i.v./1 | 35.6 (34.5, 36.7) | 0.55 (0.57, 0.54) | 1.9 (2.2, 1.7) | 7.6 (12.2, 2.9) | – | – | 467 (481, 453) | – | – |
| p.o./10b | – | – | – | – | 310 (203, 417) | 0.38 (0.5, 0.25) | 359 (296, 422) | 7.7 (6.3,9.0) | 14.7 (12.3, 17.6) | |
| p.o./10b,d | – | – | – | – | 177 (215, 138) | 0.38 (0.25, 0.50) | 380e (411, 349) | 8.1 (8.8, 7.5) | 15.8 (17.1, 14.5) |
Pharmacokinetic parameters were calculated from plasma concentration–time data and are reported as mean and individual values (n = 2). All pharmacokinetics studies were conducted in male Wistar–Han rats. Compounds 5 and 6 were dosed i.v. as a solution, in 10% DMSO/50% PEG400/40% water. Compound 12 was dosed i.v. as a solution in 10% (v/v) PEG400/90% (v/v) 23% (w/v) hydroxypropyl β-cyclodextrin (HPBCD) in water.
Oral pharmacokinetics studies were conducted in the fed state and using amorphous material unless otherwise indicated. Compounds were administered in 2% Tween 80 (v/v) in 0.5% (w/v) methyl cellulose in water either as a solution (compounds 5 and 12) or suspension (compound 6).
Crystalline.
50% ASD.
AUC0-∞.
The fraction of the oral dose absorbed (Fa × Fg) in rats was estimated using the following equation: Fa × Fg = F/(1 – CLblood/Q). CLp (after subtracting CLrenal) was converted into CLblood by dividing CLp by the rat blood to plasma ratio; compound 5 (0.821), compound 6 (0.998), compound 12 (0.777). Blood to plasma ratios were determined using previously described methods.13Q is hepatic blood flow (70 mL/min/kg) in the rat.