Activation/Inactivation of Anticancer Drugs by CYP3A4: Influencing Factors for Personalized Cancer Therapy

Abstract

Cytochrome P450 3A4 (CYP3A4), one of the most important members of the cytochrome P450 subfamily, is a crucial catalyst in the metabolism of numerous drugs. As it catalyzes numerous processes for drug activation or inactivation, the pharmacological activities and clinical outcomes of anticancer drugs metabolized by CYP3A4 are highly dependent on the enzyme's activity and expression. Due to the complexity of tumor microenvironments and various influencing factors observed in human in vitro models and clinical studies, the pharmacokinetics of most anticancer drugs are influenced by the extent of induction or inhibition of CYP3A4-mediated metabolism, and these details are not fully recognized and highlighted. Therefore, this interindividual variability due to genetic and nongenetic factors, together with the narrow therapeutic index of most anticancer drugs, contributes to their unique set of exposures and responses, which have important implications for achieving the expected efficacy and minimizing adverse events of chemotherapy for cancer in individuals. To elucidate the mechanisms of CYP3A4-mediated activation/inactivation of anticancer drugs associated with personalized therapy, this review focuses on the underlying determinants that contribute to differences in CYP3A4 metabolic activity and provides a comprehensive and valuable overview of the significance of these factors, which differs from current considerations for dosing regimens in cancer therapy. We also discuss knowledge gaps, challenges and opportunities to explore optimal dosing regimens for drug metabolic activation/inactivation in individual patients, with particular emphasis on pooling and analyzing clinical information that affects CYP3A4 activity.

Flucloxacillin Is a Weak Inducer of CYP3A4 in Healthy Adults and 3D Spheroid of Primary Human Hepatocytes

“…In contrast, prodrugs might require a lower dose due to increased formation of active metabolites and the risk of increased plasma concentrations and toxicity. This would be particularly relevant for anticancer drugs that are activated/inactivated by CYP3A4 and have a narrow therapeutic range 30 . This might also be relevant for long‐term treatment with flucloxacillin, as shown for warfarin, 10 but this will depend on the pharmacokinetic properties of the victim drug.…”

“…This would be particularly relevant for anticancer drugs that are activated/inactivated by CYP3A4 and have a narrow therapeutic range. 30 This might also be relevant for long-term treatment with flucloxacillin, as shown for warfarin, 10 but this will depend on the pharmacokinetic properties of the victim drug. Although not directly comparable, our results on CYP3A4 align with our previously published in vitro study 3 and observational data, 5,6,10,24 which have indicated that flucloxacillin is a less potent inducer of CYP enzymes than dicloxacillin.…”

Drug resistance mechanisms in cancers: Execution of pro-survival strategies

“…Furthermore, CYPs have also been shown to detoxify anticancer drugs. For instance, tamoxifen, taxanes, teniposide, gefitinib, imatinib, vinca alkaloids, and sorafenib are some drugs metabolized by CYP3A4 [ 70 ] . Another example is CYP2B6 mutations that are linked to a poor response to cyclophosphamide-based treatment in breast cancer patients, whereas CYP2D6 mutations frequently limit the anticancer effect of tamoxifen [ 71 ] .…”

Fluorescence-Based High-Throughput Assays for Investigating Cytochrome P450 Enzyme-Mediated Drug–Drug Interactions

“…Coadministration with potent CYP inhibitors or inducers may trigger pharmacokinetic drug/herb-drug interactions (DDIs/HDIs), resulting in drug accumulation or treatment failure, especially for the patients receiving some narrow therapeutic index medications (such as warfarin, digoxin, ciclosporin, etc.) (Kalra, 2007;Kumar et al, 2012;Wang et al, 2023). As a non-negligible cause of adverse drug reactions (ADRs), DDI/HDI may bring many undesirable effects or even result in deaths (Kalra, 2007;Kumar et al, 2012).…”