Table 3.
Parameters of imatinib metabolism and desmethyl imatinib metabolite formation in primary cultures of human hepatocytes treated with vehicle (DMSO), efavirenz or rifampicin and incubated with imatinib (2.5 μm)
| Imatinib | Metabolite | Imatinib | Imatinib | Imatinib | Imatinib | ||
|---|---|---|---|---|---|---|---|
| Treatment liver ID | AUC(0,24 h) (µg ml–1 h) | AUC(0,24 h) (µg ml–1 h) | AUC(0,24 h) M : P ratio | % metabolized at 24 h | t½ (h) | CLint, app (ml min–1 kg–1) | CLoral,pred (ml min–1 kg–1) |
| DMSO | |||||||
| HH 2018 | 17.6 | 5.3 | 0.30 | 64 | 17 | 1.22 | 1.19 |
| HH 2019 | 23.5 | 2.7 | 0.11 | 43 | 16 | 1.24 | 1.21 |
| Hu 1488 | 16.9 | 2.7 | 0.16 | 79 | 11 | 1.84 | 1.80 |
| Mean (95% CI) | 19.3 (13.6, 25.1) | 3.6 (1.2, 6.0) | 0.19 (0.0, 0.35) | 62 (33, 91) | 15 (10, 20) | 1.43 (0.87, 1.99) | 1.40 (0.85, 1.95) |
| Efavirenz | |||||||
| HH 2018 | 10.7 | 9.3 | 0.87 | 82 | 11 | 1.86 | 1.82 |
| HH 2019 | 6.05 | 10.4 | 1.7 | 97 | 5.3 | 3.77 | 3.69 |
| Hu 1488 | 11.9 | 10.2 | 0.86 | 88 | 8.6 | 2.34 | 2.29 |
| Mean (95% CI) | 9.55 (4.6, 14.5) | 10.0 (9.1, 10.9) | 1.1 (0.38, 1.9) | 89 (77, 101) | 8.2 (3.8, 12.6) | 2.66 (1.08, 4.24) | 2.60 (1.05, 4.14) |
| Ratio to DMSO | 0.52 (0.15, 0.90) | 3.1 (1.2, 5.0)* | 7.9 (0, 18) | 1.6 (0.57, 2.5) | 0.59 (0.21, 0.97) | 1.95 (0.42, 3.47) | 1.95 (0.42, 3.48) |
| Rifampicin | |||||||
| HH 2018 | 5.2 | 6.8 | 1.30 | 98 | 5.0 | 4.04 | 3.95 |
| HH 2019 | 8.9 | 6.7 | 0.75 | 94 | 6.0 | 3.32 | 3.25 |
| Hu 1488 | 5.5 | 6.6 | 1.19 | 99 | 4.2 | 4.79 | 4.69 |
| Mean (95% CI) | 6.5 (3.3, 9.8) | 6.7 (6.5, 6.9) | 1.1 (0.62, 1.5) | 97 (93, 101) | 5.1 (3.6, 6.5) | 4.05 (2.88, 5.22) | 3.96 (2.82, 5.11) |
| Ratio to DMSO | 0.33 (0.27, 0.40) | 2.1 (1.0, 3.2) | 6.2 (3.6, 8.8) | 1.7 (0.89, 2.4) | 0.35 (0.28, 0.42) | 2.86 (2.24, 3.48) | 2.87 (2.25, 3.49) |
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.