Abstract
Irinotecan, a camptothecin analogue, is a prodrug which requires bioactivation to form the active metabolite SN-38. SN-38 acts as a DNA topoisomerase I poison. Irinotecan has been widely used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. However, large inter-patient variability in irinotecan and SN-38 disposition, as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan. Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy. Irinotecan is subjected to be shunted between CYP3A4 mediated oxidative metabolism to form two inactive metabolites APC or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by UGT1A1 to form SN-38G. The pharmacology of this compound is further complicated by the existence of genetic inter-individual differences in activation and deactivation enzymes of irinotecan (e.g., CYP3A4, CYP3A5, UGT1A1) and sharing competitive elimination pathways with many concomitant medications, such as anticonvulsants, St. John ’ s Wort, and ketoconazole. Efflux of the parent compound and metabolites out of cells by several drug transporters (e.g., Pgp, BCRP, MRP1, MRP2) also occurs. This review highlights the latest findings in drug activation, transport mechanisms, glucuronidation, and CYP3A-mediated drug-drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent.
Keywords: Irinotecan, camptothecin, DNA topoisomerase, glucuronidation, anticonvulsants, ketoconazole, UGT1A1, SN-38G
Current Medicinal Chemistry
Title: Lessons Learned from the Irinotecan Metabolic Pathway
Volume: 10 Issue: 1
Author(s): M. K. Ma and H. L. McLeod
Affiliation:
Keywords: Irinotecan, camptothecin, DNA topoisomerase, glucuronidation, anticonvulsants, ketoconazole, UGT1A1, SN-38G
Abstract: Irinotecan, a camptothecin analogue, is a prodrug which requires bioactivation to form the active metabolite SN-38. SN-38 acts as a DNA topoisomerase I poison. Irinotecan has been widely used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. However, large inter-patient variability in irinotecan and SN-38 disposition, as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan. Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy. Irinotecan is subjected to be shunted between CYP3A4 mediated oxidative metabolism to form two inactive metabolites APC or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by UGT1A1 to form SN-38G. The pharmacology of this compound is further complicated by the existence of genetic inter-individual differences in activation and deactivation enzymes of irinotecan (e.g., CYP3A4, CYP3A5, UGT1A1) and sharing competitive elimination pathways with many concomitant medications, such as anticonvulsants, St. John ’ s Wort, and ketoconazole. Efflux of the parent compound and metabolites out of cells by several drug transporters (e.g., Pgp, BCRP, MRP1, MRP2) also occurs. This review highlights the latest findings in drug activation, transport mechanisms, glucuronidation, and CYP3A-mediated drug-drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent.
Export Options
About this article
Cite this article as:
Ma K. M. and McLeod L. H., Lessons Learned from the Irinotecan Metabolic Pathway, Current Medicinal Chemistry 2003; 10 (1) . https://dx.doi.org/10.2174/0929867033368619
DOI https://dx.doi.org/10.2174/0929867033368619 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Nifurtimox Hampered the Progression of Astroglioma <i>In vivo Via</i> Manipulating the AKT-GSK3β axis
Current Molecular Medicine Diagnostic and Therapeutic Applications of Exosome Nanovesicles in Lung Cancer: State-of-The-Art
Anti-Cancer Agents in Medicinal Chemistry Pharmacological Activation of Protein Phosphatase 2 A (PP2A): A Novel Strategy to Fight Against Human Malignancies?
Current Medicinal Chemistry Targeted Inhibition of Rictor/mTORC2 in Cancer Treatment: A New Era after Rapamycin
Current Cancer Drug Targets Bevacizumab and Angiogenesis Inhibitors in the Treatment of CNS Metastases: The Road less Travelled
Current Molecular Pharmacology Recent Advances in Antabuse (Disulfiram): The Importance of its Metal-binding Ability to its Anticancer Activity
Current Medicinal Chemistry Cryptotanshinone Induces Pro-death Autophagy through JNK Signaling Mediated by Reactive Oxygen Species Generation in Lung Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry Molecular Cytogenetics and Cytogenomics of Brain Diseases
Current Genomics Biosafety of Herpesvirus Vectors
Current Gene Therapy MYC-Mediated Synthetic Lethality for Treating Tumors
Current Cancer Drug Targets Epigenetics in Brain Tumors: HDACs Take Center Stage
Current Neuropharmacology Experimental Therapy for Lung Cancer: Umbilical Cord-Derived Mesenchymal Stem Cell-Mediated Interleukin-24 Delivery
Current Cancer Drug Targets Application of Recombinant and Non-Recombinant Peptides in the Determination of Tumor Response to Cancer Therapy
Current Pharmaceutical Biotechnology Cell-Penetrating Peptide-Mediated Therapeutic Molecule Delivery into the Central Nervous System
Current Neuropharmacology Drugs for AIDS
Mini-Reviews in Medicinal Chemistry Delivery and Application of Dietary Polyphenols to Target Organs, Tissues and Intracellular Organelles
Current Drug Metabolism Involvement of Cysteine Proteases in Cancer
Current Medicinal Chemistry Potential Anticancer Effect of Carvacrol Codrugs on Human Glioblastoma Cells
Current Drug Delivery Perspective of MiRNAs in Clinical Glioblastoma Research
Current Signal Transduction Therapy Tumour Gene Therapy Monitoring Using Magnetic Resonance Imaging and Spectroscopy
Current Gene Therapy