Competition for the Same Target In Vivo: The Competition Coefficient (R_c)

Objective: Under in vivo conditions, empirical observation of competition for the same target in different living tissues is almost impossible. Moreover, in vitro \(\mathrm{K}_{\mathrm{i}}\) (inhibition constant – see p.2) values may not correlate with in vivo results. To investigate possible in vivo competitions more realistically, the author has proposed the concept of the "competition coefficient" (\(\mathrm{R}_{\mathrm{c}}\)) and a competition rule based on it. The objective has been to theoretically determine the relationships between the competition coefficient (\(\mathrm{R}_{\mathrm{c}}\)) and ligand-target binding affinity, therapeutic effect, adverse effects, volume of distribution (\(\mathrm{V}_{\mathrm{d}}\)), selectivity, and duration of action (\(\mathrm{T}_{1/2}\)), and to apply them in clinical practice. Materials and Methods: The theoretical calculation of \(\mathrm{R}_{\mathrm{c}}\) was defined as \(\mathrm{R}_{\mathrm{c}}=\mathrm{m}_{\mathrm{act}}/\max(\mathrm{f}_{\mathrm{u}},\mathrm{f}_{\mathrm{b}})\). Various in vivo competition cases for binding to the same target were investigated. Extensive statistical analysis was performed using comparative tables of different pharmacological groups including statins, angiotensin receptor blockers, proton pump inhibitors and antipsychotics. Protein binding (PB%), free fraction (\(\mathrm{f}_{\mathrm{u}}\)), bound fraction (\(\mathrm{f}_{\mathrm{b}}\)) and number of active metabolites (\(\mathrm{m}_{\mathrm{act}}\)) were analyzed from published literature and drug databases. The relationship between \(\mathrm{R}_{\mathrm{c}}\) and pharmacokinetic parameters was evaluated. Results: Within the same pharmacological group, an increase in \(\mathrm{R}_{\mathrm{c}}\) was associated with increased ligand-target binding affinity, therapeutic effect, selectivity and prolonged duration of action (\(\mathrm{T}_{1/2}\)). The competition rule accurately predicted displacement interactions in cases where drugs share the same binding site. Comparative analysis showed consistent patterns across different drug classes. Conclusion: Instances of competition within the body can involve not only medicinal substances but also other substances capable of binding to blood proteins. Theoretical findings were consistent with established practical data. The proposed \(\mathrm{R}_{\mathrm{c}}\) may be useful for predicting drug competition, rational drug combinations and drug development.