Uniform characterization of potentiation in simple and complex situations when agents bind to different molecular sites

Abstract

There is general agreement about potentiation in dose–response studies, characterized by a left shift of the dose–response curve of A by a fixed dose of B when B is causing no effect by itself (simple situation). When B causes an effect similar to A (complex situation) by binding to different molecular sites, we propose an analogous analysis. This approach is based on comparison of experimental effects of A and B in combination with theoretical, independent effects, representing an effect of A that is not affected by B. We argue here that comparison of experimental effects with those of dose-additive (additive) combinations is inappropriate. Theoretical considerations and several practical examples show that the magnitude of effects due to additive combinations widely varies with the slope of dose–response curves of A. Consequently, it is also shown that one and the same theoretical effect may appear overadditive, additive, or underadditive. These situations are demonstrated by the experimental examples: inhibition of cytopathic effects in virus-infected cells, loss of righting reflex in mice, and smooth muscle relaxant effects of organic solvents.Key words: dose–response curves, ED₅₀, slope, independent effects, enhancement.