Metabolic behavior prediction of pazopanib by cytochrome P450 (CYP) 3A4 by molecular docking

Abstract

Metabolism-mediated drug adverse effects (e.g., drug-drug interaction, bioactivation, etc.) strongly limit the utilization of clinical drugs. The present study aims to predict the metabolic capability of cytochrome P450 (CYP) 3A4 toward pazopanib which is an excellent drug exhibiting therapeutic role toward various cancers especially for ovarian cancer. Pazopanib can be well docked into the activity cavity of CYP3A4, and the interaction structure in pazopanib was methyl group located besides nitrogen in the five-membered ring. The distance between the hydrogen atom in methyl group and active center is 3.64 Å. The interaction amino acid is Glu374. Furthermore, both pazopanib and ketoconazole were docked into the activity cavity of CYP3A4 to compare their binding potential. The distance between ketoconazole and activity center (2.10 Å) is closer than the distance between pazopanib and activity center of CYP3A4, indicating the easy influence of CYP3A4 inhibitor toward the metabolism of pazopanib. All these data were helpful for the clinical application of pazopanib, and R&D of other tinib drug candidates as new anti-tumor drugs.

Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites

“…This result is consistent with the proposal of an alcohol at C7 as a pazopanib primary metabolite in humans . It is worth mentioning that the docking of pazopanib into the active cavity of CYP3A4 showed that the methyl group at C7 was in the close vicinity of the heme (the distance between the methyl hydrogen atom and the iron being 3.64 Å) …”

Pazopanib, a novel multi-kinase inhibitor, shows potent antitumor activity in colon cancer through PUMA-mediated apoptosis

“…WT and PUMA -/- HCT-116 xenografts were established and measured as described [ 66 ]. Female 5- to 6-week-old nude mice (Vital River, China) were housed in a sterile environment with micro isolator cages and allowed access to water and chow ad libitum.…”

Establishing Transcriptional Signatures to Differentiate PXR-, CAR-, and AhR-Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes

“…PF-06282999 is a thiouracil-based irreversible inhibitor of the myeloperoxidase enzyme (Ruggeri et al, 2015;Dong et al, 2016), which induces CYP3A4 mRNA and catalytic activity via PXR (but not CAR1 or CAR3) transactivation (Moscovitz et al, 2017) and causes statistically significant decreases in the systemic exposure of CYP3A4 substrate midazolam in healthy adult subjects (Dong et al, 2017). Pazopanib, an indazolylpyrimidine-based tyrosine kinase inhibitor (TKI), is a substrate (Keisner and Shah, 2011;Liu et al, 2016) and inhibitor (Hamberg et al, 2015) of CYP3A4. In vitro studies in human hepatocytes suggest pazopanib to be a moderate inducer of CYP3A4 and CYP2B6 mRNA and catalytic activities, presumably via PXR activation (https://www.accessdata.…”