Table 4.
Enzyme | Substrate | Product | Km [μM] | Vmax [pmol/min/mg protein] | α[mg protein/g tissue] | Vmax·α/Km [mL/min/g tissue] |
Carboxylesterase | Irinotecan | SN-38 | 2.30 | 2.11 | 128 | 0.117 |
Carboxylesterase | NPC | SN-38 | 2.30 | 2.11 | 128 | 0.117 |
CYP3A4 | Irinotecan | APC | 18.4 | 26.0 | 73.3 | 0.104 |
CYP3A4 | Irinotecan | NPC | 48.2 | 74.1 | 11.7 | 0.0180 |
UGT1A1 | SN-38 | SN-38G | 3.80 | 50.8 | 750 | 10.0 |
CYP3A4 | KCZ | MOK | 0.00810 | 12.5 | 44.3 | 68.4 |
Because of the lack of experimental data, Km and Vmax values for metabolism of NPC to SN-38 by CE were assumed to be the same as those for metabolism of irinotecan to SN-38 by CE. Km and Vmax values for other reactions were obtained from the published papers [25–29]. Values of unknown parameter α were determined so that the simulation concentration/time profile fit to the experimental data published by Slatter et al. [18]. The relatively high fitted value for α in the glucronidation of SN-38 may result from the increase in UGT1A1 expression as drug response. The relatively low value for α in the oxidation of irinotecan to NPC by CYP3A4 suggests a competition in this reaction with the oxidation of irinotecan to APC by CYP3A4.