Table 2.
Chemotherapy drugs altering DMEs
| Drug | Involved DMEs | Potential mechanism of altering DMEs | Ref. |
|---|---|---|---|
| Lapatinib | CYP3A4/5 | Mechanism-based inhibition arises from the oxidation of lapatinib O-dealkylated metabolite to a quinone imine which forms quasi-irreversible metabolic intermediate complex with CYP3A4. | (105) |
| Crizotinib | CYP3A4/5 | Mechanism-based inhibition. The CYP3A inactivation is likely due to the formation of ο-quinone-imine reactive metabolites. | (93) |
| Erlotinib | CYP3A4/5, CYP2C8 | Time dependent inhibition. CYP3A4/5 inactivation is thought to involved alkyne oxidation (oxirene or ketene reactive metabolites). CYP3A inactivation occur through covalent binding of reactive metabolites to the apoprotein. | (93) |
| Saracatinib | CYP3A4 | Time dependent inhibition. Saracatinib significantly increases (up to eight-fold) the exposure of a CYP3A probe substrate. Inhibition of CYP by saracatinib involves the piperazine ring bioactivation. | (93,126) |
| Sunitinib | CYP3A4, CYP2C8 | Time dependent inhibition. Reactive metabolites formation was reported: a ρ-quinone-imine reactive metabolite arising from oxidative defluorination and an aldehyde intermediate. | (93) |
| Erlotinib | CYP3A4 | Erlotinib induced CYP3A4 gene expression slightly in human colon adenocarcinoma-derived cell line at 10μM but reduced both protein and activity levels of CYP3A4. | (93) |
| Ifosfamide | CYP3A4 | Ifosfamide increased CYP3A4 expression slightly via PXR but did not change CYP3A4 activity. | (107) |
| Flutamide | CYP3A4 | Flutamide increased CYP3A4 at mRNA, protein and activity levels in human colon cancer cell line. | (107) |
| Paclitaxel | CYP3A4, CYP3A11, UGT1A1 | Paclitaxel increased CYP3A4 at both mRNA and protein levels in a PXR-dependent manner in human cancer cells. Deficiency of TLR4 decreased paclitaxel-induced Cyp3a11 and Ugt1a1 expression in mouse hepatocytes. TLR4-PXR crosstalk leads to potential drug-drug interaction. | (59,107) |
| Thiotepa | CYP2B6 | Thiotepa is a potent noncompetitive inhibitor of CYP2B6, with Ki values of 4.8 ± 0.3 and 6.2 ± 0.7μM. | (127) |
| Docetaxel | CYP3A4 | In human liver microsomes, time-dependent inhibition of CYP3A4 activity was reported, as co-administration of docetaxel and midazolam increased the AUC of midazolam by 45.3±21.2%. However, in human cell-based assay docetaxel induced CYP3A4 expression slightly. | (107,128) |
| Sirolimus | CYP3A4 | Time dependent inhibition with IC50= 0.3±0.1μM, it causes 54.8±6.4% shift in AUC of midazolam. | (128) |
| Temsirolimus | CYP3A4 | Time dependent inhibition, it causes 56.7±5.5% shift in AUC of midazolam. | (128) |