The Tyrosine Kinase Inhibitor Nilotinib Selectively Inhibits CYP2C8 Activities in Human Liver Microsomes

Abstract

The tyrosine kinase inhibitor nilotinib was examined for its inhibition of cytochrome P450s (CYPs) in human liver microsomes and in human CYPs expressed in a baculovirus-insect cell system. Nilotinib demonstrated preferential inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation, rosiglitazone hydroxylation and amodiaquine N-deethylation in human liver microsomes, with IC₅₀ values of 0.4, 7.5 and 0.7 µM, respectively. The IC₅₀ value of nilotinib for paclitaxel 6α-hydroxylation was 20-fold lower than that of the other five tyrosine-kinase inhibitors tested. Nilotinib appears to display competitive inhibition against paclitaxel 6α-hydroxylation and amodiaquine N-deethylation, with estimated mean Ki values of 0.90 and 0.15 µM in human liver microsomes and 0.10 and 0.61 µM in recombinant human CYP2C8, respectively. These results are consistent with those of molecular docking simulations, where paclitaxel could not access the CYP2C8 catalytic site in the presence of nilotinib, but the binding of midazolam, a substrate of CYP3A4, to the catalytic site of CYP3A4 was not affected by nilotinib. The demonstrated inhibitory activity of nilotinib against CYP2C8 at concentrations less than those observed in patients who received nilotinib therapy is of potential clinical relevance and further in vivo exploration is warranted.

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

“…Judging from the K i values (Table 2), the studied kinase inhibitors displayed a wide range of inhibitory potency, among which nilotinib was the most potent inhibitor against both CYP2C8 (K i = 0.10 mM) and CYP3A4 (K i = 0.28 mM). This finding was consistent to a recent report (Kim et al, 2013). It was interesting to note that the selected kinase inhibitors displayed pathway-dependent inhibition toward CYP2C8-and CYP3A4-mediated paclitaxel hydroxylation.…”

The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

“…S3B) cast further doubt on this hypothesis for the enhanced activity of this combination. Another potential mechanism of action might be the known inhibition by nilotinib of the cytochrome P450s (including CYP2C8) involved in the metabolism of paclitaxel (48), which would increase systemic paclitaxel exposure; however, we also found comparable plasma paclitaxel concentrations in MDA-MB-468 xenograft models treated with paclitaxel alone versus the nilotinib-paclitaxel combination (data not shown), rendering this hypothesized mechanism of action also unlikely.…”

A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment

“…Amodiaquine N-deethylation [18,40,41] Paclitaxel 6α-hydroxylation [40,42] Gemfibrozil [43] Rifampicin [34,36,44] Montelukast [45] Phenelzine [46] 2C9 Diclofenac 4 ′ -hydroxylation [18,[47][48][49] Sulfaphenazole [18,[49][50][51] Rifampicin [34,36,44,52] S-warfarin 7-hydroxylation [48] Tienilic acid [17,53] 2C19 S-mephenytoin 4 ′ -hydroxylation [54] N-3-benzylnirvanol [55] Rifampicin [36] Ticlopidine [51,56] Loratadine [57] Nootkatone [58] 2D6 Bufuralol 1 ′ -hydroxylation [49,59] Quinidine [18,49,60,61] Dextromethorpan O-demethylation [18,62] Paroxetine [61,63] 3A4/5 Midazolam 1 ′ -hydroxylation [17,49,[64][65][66] Ketoconazole…”