Drug Synergy and Antagonism: Molecular and Cellular Mechanisms of Drug Combination Effects

David Aphkhazava; Maia Nozadze; Mzia Tsiklauri; Manana Makharadze; Maia Berodze; Nodar Sulashvili; Giorgi Margvelani; Anushka Rohidas Temgire; Arfan Imtiaz Abdul Samad; Neha Neelofar; Tharushi Anargali Silva; Oluwadamilola Pentho Nudegbesi; Muskan Khan; Vedant Anilkumar Malekar; Aayushi Thakur; Janhavi Deepak Doshi; Nino Maziashvili; Lolita Shengelia; George Maglakelidze; Ilia Atanelishvili

Authors

David Aphkhazava PhD, Professor, University of Georgia, Tbilisi, Georgia. Orcid: https://orcid.org/0000- 0001- 6216-64
Maia Nozadze PhD, Professor, University of Georgia, Tbilisi, Georgia
Mzia Tsiklauri PhD, Affiliated Professor of the Medical Programs of Gr.Robakidze University, Microbiology, Immunology, Virology, Infection Control. Invited Professor of the Medical Programs of Alte University, Tbilisi, Georgia. Invited Professor of the Medical Programs of Caucasus International University, Laboratory Medicine, Tbilisi, Georgia. Member of the Georgian Immunologists Association, Member of the Accreditation Council of the Quality Development, Center of the Ministry of Education of Georgia
Manana Makharadze Prof. David Agmashenebeli University of Georgia, Tbilisi, Georgia.
Maia Berodze Assistant Professor at Caucasus International University, Tbilisi, Georgia
Nodar Sulashvili MD, PhD, Doctor of Pharmaceutical and Pharmacological Sciences In Medicine, Invited Lecturer (Professor) of Scientific Research-Skills Center at Tbilisi State Medical University; Professor of Medical and Clinical Pharmacology of International School of Medicine at Alte University; Professor of Pharmacology of Faculty of Medicine at Georgian National University SEU, Associate Affiliated Professor of Medical Pharmacology of Faculty of Medicine at Sulkhan-Saba Orbeliani University; Associate Professor of Medical Pharmacology at School of Medicine at David Aghmashenebeli University of Georgia; Associate Professor of Biochemistry and Pharmacology Direction of School of Health Sciences at the University of Georgia. Associate Professor of Pharmacology of Faculty Dentistry and Pharmacy at Tbilisi Humanitarian Teaching University; Tbilisi, Georgia; Orcid: https://orcid.org/0000-0002-9005-8577.
Giorgi Margvelani Prof. European University, Tbilisi, Georgia.
Anushka Rohidas Temgire Alte University, Tbilisi, Georgia
Arfan Imtiaz Abdul Samad University of Georgia, Tbilisi, Georgia
Neha Neelofar UAE University, United Arab Emirates
Tharushi Anargali Silva Alte University, Tbilisi, Georgia
Oluwadamilola Pentho Nudegbesi Alte University, Tbilisi, Georgia
Muskan Khan Alte University, Tbilisi, Georgia
Vedant Anilkumar Malekar Alte University, Tbilisi, Georgia
Aayushi Thakur University of Georgia, Tbilisi, Georgia
Janhavi Deepak Doshi Alte University, Tbilisi, Georgia
Nino Maziashvili Associate Professor, University of Georgia, Tamar Gagoshidze Neuropsychology Center, Tbilisi, Georgia
Lolita Shengelia PhD, Invited lecturer of Georgian National University, Tbilisi, Georgia; Invited lecturer of Georgian American University, Tbilisi, Georgia
George Maglakelidze PhD, Professor, University of Georgia, Tbilisi, Georgia
Ilia Atanelishvili Medical University of South Carolina, Charleston, SC, USA

Keywords:

drug synergy, antagonism, combination therapy, combination index, Loewe additivity, Bliss independence, synthetic lethality, pharmacokinetic interactions, network pharmacology, drug resistance

Abstract

The combined administration of therapeutic agents is a foundational strategy of modern pharmacology, yet the distinction between a clinically successful drug combination and a harmful or ineffective one rests on complex molecular and cellular phenomena. This review synthesizes current understanding of drug synergy and antagonism, beginning with the quantitative frameworks, including Loewe additivity, Bliss independence, the combination index method, and isobolographic analysis, that allow synergism and antagonism to be defined and measured in a scientifically rigorous manner. The molecular and cellular mechanisms that generate supra-additive or sub-additive effects are then examined across therapeutic domains. In oncology, synergy arises from parallel pathway blockade, synthetic lethality, DNA damage response manipulation, apoptotic priming, and reversal of multidrug resistance; in infectious disease, it emerges from sequential blockade of biosynthetic pathways, enhanced intracellular drug accumulation, and drug-induced sensitization. Pharmacokinetic mechanisms, including cytochrome P450 inhibition and induction, transporter-mediated interactions, and altered distribution, are distinguished from true pharmacodynamic interactions at target level. Antagonism, long considered a purely undesirable outcome, is analyzed mechanistically and reinterpreted in light of evolutionary studies showing that antagonistic interactions can restrain the emergence of resistance. Systems-level perspectives, including network pharmacology and higher-order interaction analysis, are integrated throughout. Finally, the methodological pitfalls that afflict combination studies, the challenges of clinical translation, and emerging strategies for rational combination design are critically appraised. A central conclusion is that synergy is not a property of two molecules alone but of a drug pair acting within a defined biological, genetic, and physiological context.

Drug Synergy and Antagonism: Molecular and Cellular Mechanisms of Drug Combination Effects

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