Table 1.
Selected topotecan lactone pharmacokinetic parameters in ABC transporter KO strains at two i.v. dose levels.
| Parameters (TPT Lactone) | Mouse Strains | |||||||
|---|---|---|---|---|---|---|---|---|
| C57/BL6 | Abcc2−/− | Abcc4−/− | Abcb1−/− | Abcg2−/− | Abcc2; Abcg2−/− | Abcc4; Abcg2−/− | Abcc2; Abcb1−/− | |
|
| ||||||||
| (n=7) | (n=6) | (n=6) | (n=5) | (n=7) | (n=5) | (n=5) | (n=5) | |
| 1 mg | ||||||||
| Vd(l/kg) | 19.5 ± 5.6 | 17.9 ± 8.1 | 20.4 ± 5.5 | 14.0 ± 2.5 | 9.9 ± 4.3* | 7.1 ± 1.9**, ## | 9.1 ± 2.5*,‡‡ | 9.0 ± 2.7* |
| CL (l/hr/kg) | 12.8 ± 3.0 | 9.2 ± 3.9 | 14.2 ± 7.8 | 7.0 ± 2.2 | 4.9 ± 2.9** | 3.6 ± 1.0** | 5.1 ± 0.7‡ | 5.8 ± 0.8* |
| t1/2 (hr) | 1.1 ± 0.3 | 1.4 ± 0.2 | 1.3 ± 0.8 | 1.4 ± 0.2 | 1.5 ± 0.4 | 1.4 ± 0.3 | 1.2 ± 0.3 | 1.1 ± 0.4 |
| AUCInf (hr*ng/ml) | 81.9 ± 17.4 | 130.1 ± 65.0 | 91.2 ± 51.2 | 154.0 ± 46.7 | 242.4 ± 75.8*** | 291.5 ± 76.2***,### | 200.0 ± 25.5*,‡ | 175.7 ± 23.1 |
| Renal (fu, %) | 15.1 ± 9.3 | 21.8 ± 8.5 | 12.5 ± 6.7 | 24.0 ± 12.2 | 31.7 ± 9.1* | 37.9 ± 9.6** | 32.5 ± 8.1* | 25.4 ± 11.1 |
| Fecal (ff, %) | 35.7 ± 19.3 | 26.1 ± 12.5 | 44.7 ± 17.7 | 13.3 ± 11.4 | 19.1 ± 16.8 | 11.0 ± 4.9 | 14.3 ± 7.2 | 21.2 ± 5.6 |
|
| ||||||||
| 4 mg | (n=7) | (n=6) | (n=6) | (n=5) | (n=7) | (n=5) | (n=5) | (n=5) |
|
|
||||||||
| Vd(l/kg) | 23.6 ± 6.7 | 33.3 ± 10.2 | 21.7 ± 3.8 | 14.9 ± 5.4 | 10.5 ± 2.6* | 7.9 ± 3.8**,### | 9.5 ± 4.1* | 13.6 ± 12.5### |
| CL (l/hr/kg) | 14.0 ± 5.3 | 19.1 ± 7.9 | 15.9 ± 4.7 | 11.4 ± 2.8 | 5.9 ± 1.6* | 4.0 ± 0.6**,### | 6.5 ± 2.2‡ | 5.9 ± 0.5*,### |
| t1/2 (hr) | 1.3 ± 0.6 | 1.4 ± 0.9 | 1.0 ± 0.2 | 0.9 ± 0.2 | 1.2 ± 0.2 | 1.3 ± 0.4 | 1.0 ± 0.1 | 1.5 ± 1.2 |
| AUCInf (hr*ng/ml) | 314.3 ± 101.3 | 240.6 ± 94.3 | 271.3 ± 81.5 | 372.3 ± 105.4 | 735.6 ± 270.7*** | 1021.9 ± 151.2***,### | 684.0 ± 244.3**,‡‡ | 676.4 ± 55.8**,## |
| Renal (fu, %) | 18.0 ± 11.8 | 16.5 ± 9.9 | 18.8 ± 11.9 | 14.7 ± 7.8 | 32.6 ± 18.1 | 34.7 ± 5.1 | 30.7 ± 11.9 | 35.7 ± 11.3 |
| Fecal (ff, %) | 25.5 ± 10.4 | 18.0 ± 9.7 | 24.2 ± 16.5 | 12.1 ± 8.8 | 12.0 ± 9.8 | 4.9 ± 2.7* | 12.5 ± 6.9 | 5.9 ± 3.3* |
Topotecan lactone pharmacokinetic parameters - volume of distribution (Vd), systemic clearance (CL), elimination half life (t1/2) area under the plasma curve at infinity (AUCinf), renal fraction of dose (fu, %), fecal fraction of dose (ff, %) in male C57BL/6 (WT), Abcc2−/−, Abcc4−/−, Abcb1−/−, Abcg2−/−, Abcc2;Abcg2, Abcc4;Abcg2−/− and Abcc2;Abcb1−/− mice, after IV administration of 1 mg/kg and 4 mg/kg topotecan. The pharmacokinetic parameters were analyzed by noncompartmental analysis using WinNonlin Professional Version 5.2. The statistical differences were determined using the One-Way ANOVA with Tukey's multiple comparison (GraphPad Prism version 5.04) tests to compare inter-strain differences. Data are expressed as mean values of the Vd, CL, AUC, t1/2, fu, %, ff, %±SD (n = 5–7;
P < 0.05
P < 0.01
P < 0.001 compared with wild-type
P < 0.05
P < 0.01
P < 0.001 compared with Abcc2−/−
P < 0.05
P < 0.01
P < 0.001 compared with Abcc4−/−).