Table 3.
Pharmacokinetic parameters of Gem, dFdU, and V-Gem following IV (76 nmol/g) and PO (228 nmol/g) administrations of Gem and V-Gem in mice (n = 4).
| Treatment | Parameter | Analyte | ||
|---|---|---|---|---|
| Gemcitabine | dFdU | Prodrug | ||
| Gem IV (76 nmol/g) | AUC0_6 hr (min × μM) | 1621 (38%) | 2218 (54%) | - |
| AUCinf (min × μM) | 1628 (38%) | 2484 (65%) | - | |
| % Extrapolated | 0.4 (40%) | 8.2 (88%) | - | |
| T1/2 (min) | 42.5 (44%) | 106 (32%) | - | |
| Tmax (min) | - | 30 (30 – 45) | - | |
| Cmax (μM) | 67.2 (30%)† | 15.5 (34%) | - | |
| CL (mL/hr/g) | 2.8 (38%) | - | - | |
| Vss (mL/g) | 1.4 (44%) | - | - | |
| Gem PO (228 nmol/g) | AUC0–6 hr (min × μM) | 887 (55%) | 6091 (15%) | - |
| AUCinf (min × μM) | 893 (55%) | 8613 (22%) | - | |
| % Extrapolated | 0.6 (55%) | 26.2 (52%) | - | |
| T1/2 (min) | 29.8 (41%) | 210 (41%) | - | |
| Tmax (min) | 30 (15 – 45) | 45 (30 – 120) | - | |
| Cmax (μM) | 9.8 (42%) | 35.3 (30%) | - | |
| Foral | 18.3% | - | - | |
| V-Gem IV (76 nmol/g) | AUC0–6 hr (min × μM) | 794 (23%) | 2017 (49%) | 103 (101%) |
| AUCinf (min × μM) | 801 (22%) | 2345 (61%) | 106 (98%) | |
| % Extrapolated T1/2 (min) | 0.8 (92%) 46.2 (34%) | 11.3 (84%) 128 (38%) | 1.1 (253%) 3.7 (33%) | |
| Tmax (min) | 2 (2 – 2) | 22.5 (15 – 30) | - | |
| Cmax (μM) | 41.6 (26%) | 13.9 (31%) | 32.7 (139%)† | |
| CL (mL/hr/g) | - | - | 43.1 (98%) | |
| Vss (mL/g) | - | - | 2.4 (145%) | |
| V-Gem PO (228 nmol/g) | AUC0–6 hr (min × μM) | 806 (27%) | 7732 (19%) | 1.9 (113%) |
| AUCinf (min × μM) | 814 (27%) 0.9 | 11,125 (24%) 30.2 | CND | |
| % Extrapolated | (17%) | (13%) | CND | |
| T1/2 (min) | 39.1 (25%) | 216 (9%) | CND | |
| Tmax (min) | 15 (5 – 30) | 30 (15 – 30) | 3.5 (2 – 5) | |
| Cmax (μM) | 11.1 (24%) | 47.9 (6%) | 0.2 (101%) | |
| Foral | 16.7% | - | 0.6% | |
Parameters are reported as geometric mean (geometric CV%), except for Tmax, which is reported as median (min – max), and oral bioavailability (Foral), which is reported as the dose normalized ratio (oral/IV) of the geometric mean AUCinf.
†
C0 reported for Cmax. CND, could not be determined; IV, intravenous; PO, oral; Gem, gemcitabine; dFdU, 2’,2’-difluorodeoxyuridine; V-Gem, 5’-l-valyl-gemcitabine.