Enzyme and Transporter Kinetics for CPT-11 (Irinotecan) and SN-38: An Insight on Tumor Tissue Compartment Pharmacokinetics Using PBPK
| Autor: | Zhuo X Wu, Martin Czejka, Mansoor Ahmed, Dong H Yang, Rafeeq Alam Khan, Zhe S Chen, Najia Mansoor, Tasneem Ahmad, Yingfang Fan, Syed Sharib |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Cancer Research Physiologically based pharmacokinetic modelling Metabolic Clearance Rate Metabolite Population Biological Availability SN-38 Pharmacology Irinotecan 030226 pharmacology & pharmacy Catalysis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Neoplasms Drug Discovery Humans Computer Simulation Tissue Distribution Whole Body Imaging Pharmacology (medical) Compartment (pharmacokinetics) education Active metabolite ADME education.field_of_study General Medicine Middle Aged Enzymes Kinetics Oncology chemistry 030220 oncology & carcinogenesis Inactivation Metabolic Female Carrier Proteins Protein Binding |
| Zdroj: | Recent Patents on Anti-Cancer Drug Discovery. 14:177-186 |
| ISSN: | 1574-8928 |
| DOI: | 10.2174/1574892814666190212164356 |
| Popis: | Background:Computational tools are becoming more and more powerful and comprehensive as compared to past decades in facilitating pharmaceutical, pharmacological and clinical practice. Anticancer agents are used either as monotherapy or in combination therapy to treat malignant conditions of the body. A single antineoplastic agent may be used in different types of malignancies at different doses according to the stage of the disease.Objective:To study the behavior of CPT-11 (Irinotecan) and its metabolite SN-38 in tumor tissue compartment through the Whole Body-Physiologically Pharmacokinetics (WB-PBPK) and to determine the activity of metabolic enzymes and transporters participating in the disposition of CPT-11 and SN-38 working in their physiological environment inside the human body.Methods:Whole body PBPK approach is used to determine the activity of different metabolic enzymes and transporters involved in the disposition of CPT-11 and its active metabolite, SN-38. The concentrations and pharmacokinetic parameters of the parent compound and its metabolite administered at clinically applicable dose via the intravenous route in the tumor tissue are predicted using this approach.Results:The activity rate constants of metabolic enzymes and transporters of CPT-11 are derived at their natural anatomic locations. Concentration-time curves of CPT-11 and SN-38 with their 5th to 95th percentage range are achieved at the tumor tissue level. Mean tumor tissue pharmacokinetics of both compounds are determined in a population of 100 individuals.Conclusion:Tumor tissue concentration-time curves of CPT-11 and SN-38 can be determined via PBPK modeling. Rate constants of enzymes and transporters can be shown for healthy and tumor bearing individuals. The results will throw light on the effective concentration of active compound at its target tissue at the clinically applied IV dose. |
| Databáze: | OpenAIRE |
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