Inhibition of Cytochrome P450 Enzyme and Drug-Drug Interaction Potential of Acid Reducing Agents Used in Management of CDK Inhibitors for Breast Cancer Chemotherapy

Patil, Prajakta Harish and Jagadish, PC and Fajeelath, Fatima and Birangal, Sumit and Shenoy, Gurupur G and Rao, Mahadev (2022) Inhibition of Cytochrome P450 Enzyme and Drug-Drug Interaction Potential of Acid Reducing Agents Used in Management of CDK Inhibitors for Breast Cancer Chemotherapy. Current Drug Metabolism, 23. pp. 137-149. ISSN 1389-2002

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Abstract

Background and Objective: Concurrent usage of proton pump inhibitors and their effect on survival and medication termination has been found in individuals receiving protein kinase inhibitor chemotherapy. To investigate the drug-drug interaction mechanism between CDK inhibitors and proton pump inhibitors, the in-silico docking approach was designed by applying computer simulation modules to predict the binding and inhibitory potential.Methods: The interaction potential of proton pump inhibitors and CDK inhibitors was predicted utilising molecular docking techniques that employed Schrödinger algorithms to capture the dynamics of the CYP450 enzyme-inhibitor interaction between proton pump inhibitors and CDK inhibitors. Additionally, the human liver microsomes assay was used to determine the in vitro half-maximal inhibitory concentration (IC50) of proton pump inhibitors and the inactivation of CDK inhibitors via CYP3A4.Results:Proton pump inhibitors alter the conformation of the CYP3A4 and CYP2C19 enzymes and interact with the heme prosthetic group, as determined by docking studies. It may result in the suppression of CDK inhibitors' metabolism via competitive inhibition at the binding site of an enzyme. Omeprazole and rabeprazole both significantly block midazolam's 1′-hydroxylation by CYP3A4 in vitro, with IC50 values of 9.86μM and 9.71μM, respectively. When omeprazole and rabeprazole are co-incubated in human liver microsomes at a 30μM concentration equivalent to the Cmax of omeprazole and rabeprazole, rabeprazole significantly prolongs the metabolic clearance of palbociclib,whereas omeprazole affects the ribociclib CYP3A4-mediated metabolism.Conclusion: Using dynamic models, we determined that proton pump inhibitors such as rabeprazole and omeprazole indeed have the potential to cause clinically significant drug-drug interactions with CDK inhibitors in the treatment of estrogen receptor (ER) positive and HER2-positive breast cancer. As a result, it is suggested to use caution when prescribing proton pump inhibitors to these individuals

Item Type: Article
Uncontrolled Keywords: CDK inhibitors; CYP450; Drug-drug interactions; HER2-positive breast cancer; Ligand-based docking; Proton pump inhibitors; Human liver microsomes; Metabolic stability
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmacy Practice
Depositing User: KMC Library
Date Deposited: 09 Sep 2022 08:37
Last Modified: 09 Sep 2022 08:37
URI: http://eprints.manipal.edu/id/eprint/159293

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