Biochemical Pathways in Drug-Drug Interactions: A Pharmacological Perspective for Enhanced Drug Safety and Efficacy-Cytochrome Inhibition Mechanisms

Alalyani, Mohammed Qublan; Al dosari, Yasser Mohammed; Oteif, Reem Mohammed; Hilbah, Mohammed Ahmad Ezzi; Hakami, Emad Ail Ayoub; Zedin, Nouf Ali; Alqahl, Sultan Ali; Alfaifi, Yahya Mohammed; Almutairi, Ali  Nowifa; Alsahali, Falah Falih; Ageeli, Taibah Mousa Rabea; Albidah, Mohammed Badah; Aldossery, Wadha Meflah; Bajbair, Ahmed Abu Bakr; Al-Maghribi, Randa Abdel Qader Ahmed

doi:10.21608/ejchem.2024.336321.10804

	Biochemical Pathways in Drug-Drug Interactions: A Pharmacological Perspective for Enhanced Drug Safety and Efficacy-Cytochrome Inhibition Mechanisms
Egyptian Journal of Chemistry
Volume 67, Issue 13, December 2024, Page 1507-1517 PDF (899.28 K)
Document Type: Review Articles
DOI: 10.21608/ejchem.2024.336321.10804
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Authors
Mohammed Qublan Alalyani ¹; Yasser Mohammed Al dosari²; Reem Mohammed Oteif³; Mohammed Ahmad Ezzi Hilbah⁴; Emad Ail Ayoub Hakami⁵; Nouf Ali Zedin⁶; Sultan Ali Alqahl⁷; Yahya Mohammed Alfaifi⁸; Ali Nowifa Almutairi⁹; Falah Falih Alsahali¹⁰; Taibah Mousa Rabea Ageeli¹¹; Mohammed Badah Albidah¹²; Wadha Meflah Aldossery¹³; Ahmed Abu Bakr Bajbair¹⁴; Randa Abdel Qader Ahmed Al-Maghribi¹⁵
¹Al Bashair Hospital, Ministry of Health, saudi Arabia
²Wadi Al Dwasir General Hospital, Ministry of Health, saudi Arabia
³Jazan Health Cluster, Ministry of Health, saudi Arabia
⁴Jazan Health Complex, Ministry of Health, saudi Arabia
⁵Jazan Specialized Hospital, Ministry of Health, saudi Arabia
⁶Upper Baydah Primary Health Care Center, Ministry of Health, saudi Arabia
⁷Ahad Almsarha Hospital, Ministry of Health, saudi Arabia
⁸Riyadh Third Health Cluster, Ministry of Health, saudi Arabia
⁹Ad Diriya Hospital, Ministry of Health, saudi Arabia
¹⁰Hotat Sudir Hospital, Ministry of Health, saudi Arabia
¹¹Prince Mohammad Bin Nasser Hospital, Ministry of Health, saudi Arabia
¹²Zulfi General Hospital, Ministry of Health, saudi Arabia
¹³King Salman Hospital, Ministry of Health, saudi Arabia
¹⁴Primary health care center in Alhoma, Ministry of Health, saudi Arabia
¹⁵Jeddah Health Affairs Directorate, Ministry of Health, saudi Arabia
Abstract
Background: Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism of many drugs, and their inhibition can lead to significant drug-drug interactions (DDIs). Understanding the biochemical pathways involved in CYP inhibition is essential for improving drug safety and efficacy. This review explores the mechanisms of CYP inhibition, reaction phenotyping, and predictive models used to assess drug interactions, with a focus on high-throughput screening, probe assays, and modeling approaches. Aim: This review aims to provide a comprehensive understanding of CYP inhibition mechanisms, with an emphasis on assessing and predicting drug-drug interactions. It examines in vitro methods, the implications of CYP inhibition in clinical practice, and the use of predictive models to identify potential drug interactions early in the drug development process. Methods: We conducted a literature review on current methodologies for assessing CYP inhibition, including early high-throughput screening using fluorescent and luminescent assays, probe assays with human liver microsomes (HLM), and model-based approaches. Emphasis was placed on the validation of these methods, limitations associated with each approach, and their predictive capabilities. The use of CYP inhibition assays in combination with predictive modeling techniques, such as ligand- and structure-based models, was also explored. Results: The review highlighted several methods for assessing CYP inhibition, including the use of cocktail assays, recombinant enzymes, and high-throughput screening. Despite the advantages of these techniques, challenges remain in ensuring substrate selectivity and overcoming limitations such as metabolic pathway complexity and the potential for non-specific inhibition. The application of predictive models, using databases and structural simulations, was found to offer promising tools for early DDI prediction and risk assessment. Conclusion: Understanding CYP inhibition mechanisms is crucial for optimizing drug safety and efficacy. High-throughput screening, probe assays, and predictive modeling techniques provide valuable insights into potential DDIs. However, challenges remain in refining these methods to enhance their predictive accuracy and applicability in clinical settings. Continued advancements in these areas are essential for improving drug development processes and minimizing adverse drug interactions.
Keywords
Cytochrome P450; drug-drug interactions; CYP inhibition; high-throughput screening; probe assays; predictive modeling; drug safety


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