Figure 1.
Sorafenib metabolism by CYP3A4 (A–E) and CYP3A4 protein expression (F) in pooled NHLMs, THLMs and CHLMs.
The formation rate of M2 expressed as pmol/mg/min (mean ± SD), other metabolites rates (M1, M3, M4 and M5) expressed as peak area ratio (mean ± SD). All the experiments were carried out in triplicate. One-way ANOVA, with or without Tukey–Kramer multiple comparison (post-hoc) tests, was used for data analysis. “*” denotes statistical significance (P<0.05); “**” denotes statistical significance (P<0.01), “***” denotes statistical significance (P<0.001).
Table 1.
Kinetic parameters of sorafenib calculated by M2 formation in pooled NHLMs, THLMs and CHLMs.
Table 2.
Kinetic parameters of sorafenib calculated by other CYP3A4 mediated metabolites in pooled NHLMs, THLMs and CHLMs.
Figure 2.
Inter-individual variability of sorafenib metabolism by CYP3A4 with 18 human liver microsomes samples (THLMs and NHLMs).
Sorafenib (15 µM) was incubated with the microsomes obtained from different patients for 90 min at 37°C (the micorsome concentration was 0.4 mg/ml). The formation rate of M2 expressed as pmol/mg/min (mean ± SD), other metabolites rates (M1, M3, M4 and M5) expressed as peak area ratio (mean ± SD). All the experiments were performed in triplicate. Student’s T-test analysis was used for data analysis. “*” denotes statistical significance (P<0.05).
Figure 3.
Sorafenib metabolism by UGT1A9 (A) and UGT1A9 protein expression (B) in pooled NHLMs, THLMs and CHLMs.
The formation rate of M7 expressed as peak area ratio (mean ± SD). All the experiments were carried out in triplicate. One-way ANOVA, with or without Tukey–Kramer multiple comparison (post-hoc) tests, was used for data analysis. “*” denotes statistical significance (P<0.05); “**” denotes statistical significance (P<0.01), “***” denotes statistical significance (P<0.001).
Table 3.
Kinetic parameters of sorafenib glucuronidation calculated by M7 formation in pooled NHLMs, THLMs and CHLMs.
Figure 4.
Inter-individual variability of sorafenib metabolism by UGT1A9 with 18 human liver microsomes samples (THLMs and NHLMs).
Sorafenib (2.5 µM) was incubated with microsomes (0.133 mg/ml) obtained from different patients for 90 min at 37°C. The formation rate of M7 expressed as peak area ratio (mean ± SD). All the experiments were performed in triplicate. Student’s T-test analysis was used for data analysis. “*” denotes statistical significance (P<0.05).