Table 2.
Parameters of imatinib metabolism and desmethyl imatinib metabolite formation in primary cultures of human hepatocytes treated with vehicle (DMSO), ritonavir or ketoconazole and incubated with imatinib (2.5 μm).
| Imatinib | Metabolite | Imatinib | Imatinib | Imatinib | Imatinib | ||
|---|---|---|---|---|---|---|---|
| Treatment liver ID | AUC(0,48 h) (µg ml–1 h) | AUC(0,48 h) (µg ml–1 h) | AUC(0,48 h) M : P ratio | % metabolized at 48 h | t½ (h) | CLint, app (ml min–1 kg–1) | CLoral,pred (mL/min/kg) |
| DMSO | |||||||
| Hu 1595 | 16.7 | 8.4 | 0.51 | 86 | 17 | 1.17 | 1.15 |
| Hu 1600 | 25.3 | 5.8 | 0.23 | 73 | 26 | 0.78 | 0.76 |
| H 1165 | 33.9 | 4.4 | 0.13 | 77 | 24 | 0.84 | 0.82 |
| H 1174 | 28.0 | 5.9 | 0.21 | 82 | 19 | 1.03 | 1.00 |
| Mean (95% CI) | 26.0 (14.6, 37.4) | 6.1 (3.5, 8.8) | 0.27 (0, 0.53) | 80 (71, 89) | 22 (15, 28) | 0.96 (0.67, 1.24) | 0.93 (0.65-1.21) |
| Ritonavir | |||||||
| Hu 1595 | 26.2 | 4.3 | 0.16 | 77 | 23 | 0.88 | 0.86 |
| Hu 1600 | 43.4 | 0.94 | 0.022 | 40 | 64 | 0.32 | 0.31 |
| H 1165 | 46.6 | 1.7 | 0.036 | 51 | 49 | 0.41 | 0.40 |
| H 1174 | 51.1 | 0.90 | 0.018 | 29 | 104 | 0.19 | 0.19 |
| Mean (95% CI) | 41.8 (24.5, 59.1) | 2.0 (0, 4.5) | 0.059 (0, 0.17) | 49 (17, 82) | 60 (6, 114) | 0.45 (0, 0.93) | 0.44 (0-0.96 |
| Ratio to DMSO | 1.62 (1.31, 1.93) | 0.30 (0.02, 0.58) | 0.19 (0.003, 0.38)* | 0.62 (0.26, 0.98) | 2.8 (0, 5.6)* | 0.46 (0.09, 0.83)* | 0.46 (0.09-0.83)* |
| Ketoconazole | |||||||
| Hu 1595 | 26.7 | 5.3 | 0.20 | 77 | 23 | 0.89 | 0.87 |
| Hu 1600 | 58.2 | 1.7 | 0.028 | 10 | 210 | 0.10 | 0.093 |
| H 1165 | 48.5 | 5.1 | 0.11 | 61 | 32 | 0.62 | 0.61 |
| H 1174 | 55.1 | 0.88 | 0.016 | 25 | 100 | 0.20 | 0.20 |
| Mean (95% CI) | 47.1 (24.5, 69.7) | 3.2 (0, 6.9) | 0.088 (–0, 0.22) | 43 (0, 9.3) | 91 (0, 229) | 0.45 (0, 1.0) | 0.44 (0-1.0) |
| Ratio to DMSO | 1.82 (1.21, 2.44)* | 0.56 (0, 1.3) | 0.36 (0, 0.92) | 0.53 (0, 1.1) | 4.0 (0, 11) | 0.46 (0, 1.0) | 0.46 (0-1.0)** |
M : P ratio, the ratio of desmethyl imatinib to imatinib.
*P < 0.05 vs. DMSO, non-parametric Friedman anova followed by Dunn's multiple comparison test.
**The individual ratios to DMSO were 0.76, 0.12, 0.74 and 0.20 for a mean of 0.46. This corresponds to a fold decrease in clearance (inverse of the ratio) of 1.3, 8.2, 1.3 and 5.0 for a mean of 4.0.