Table 2. Michaelis-Menten kinetic parameters.
| Affinity Constant, Km [µM] | Relative Intrinsic Clearance [fold diff.] | ||||||||
| PKI | metabolites | CYP | CYP | ||||||
| 1A1 | 1B1 | 2J2 | 3A4 | 1A1 | 1B1 | 2J2 | 3A4 | ||
| Dasatinib | dehydroxyethyl-dasatinib | 4.7 | 2.2 | 3.9 | 71.4 | 0.5 | 1.1 | 0.5 | 1.0 |
| Imatinib | N-demethyl-imatinib | 7.6 (*) | / | 1.7 | 2.3 | 0.2 (*) | 0.4 | 1.0 | |
| OH-imatinib #3 | 3.4 (*) | / | / | 3.4 | 2.6 (*) | 1.0 | |||
| OH-imatinib #5 | 4.0 (*) | 5.5 (*) | 2.3 | 3.1 | 2.9 (*) | 4.5 (*) | 0.3 | 1.0 | |
| NO-imatinib #6 | / | / | 0.6 | 2.2 | 0.9 | 1.0 | |||
| NO-imatinib #7 | 1.0 (*) | 7.5 (*) | 0.4 | 5.3 | 27.9 (*) | 0.6 (*) | 4.0 | 1.0 | |
| NO-imatinib #8 | / | / | / | 2.9 | 1.0 | ||||
| Nilotinib | NO-nilotinib #1 | 3.0 | / | 0.8 | 27.6 | 0.5 | 1.3 | 1.0 | |
| OH-nilotinib #2 | 4.0 | / | 0.7 | 9.8 | 0.0 | 3.6 | 1.0 | ||
| Sorafenib | NO-sorafenib #1 | / | / | / | 6.1 | 1.0 | |||
| OH-sorafenib #2 | 1.6 | / | 1.5 | 5.4 | 0.2 | 3.9 | 1.0 | ||
| Sunitinib | E-deethyl-sunitinib #1 | 6.9 | 2.7 | 89.1 | 13.8 | 0.1 | 0.1 | 0.2 | 1.0 |
| Z-deethyl-sunitinib #2 | 6.7 | 2.7 | 80.7 | 13.2 | 0.2 | 0.1 | 0.2 | 1.0 | |
Michaelis-Menten kinetic parameters determined in microsome incubations with cDNA expressed CYP1A1, 1B1, 2J2 and 3A4 isozymes. A) Affinity constants, Km in µM, for different TKI metabolic pathways. B) Relative intrinsic clearance (Vmax/Km; in arbitrary unit [arb]) for the same TKI metabolic pathways, expressed as fold differences of the intrinsic clearance of CYP3A4, the major hepatic enzymes involved in TKI degradation. Abbreviations: OH-: hydroxyl-metabolites, NO-: N-oxide metabolite. Imatinib metabolites are numbered in accordance to [18].
(*)
Results obtained in our previous published study [18].