Comparison of applicability of different methods for drug combination studies Modified from “Quantitation of Synergism and Antagonism of Two or More Drugs by Computerized Analysis,” in Synergism and Antagonism in Chemotherapy (Chou TC and Rideout DC eds) pp 223–244. Copyright 1991 with permission from Elsevier.

Nature of Dose-Effect Curves and Drug Interactions
Mutually exclusive (similar mode of action)a Mutually nonexclusive (independent mode of action)b
First orderc Higher orderd First orderc Higher orderd
Webb's fractional product methode No No Yes No
Loewe's isobologram methodf Yes Yes No No
Multiple drug effect equationg Yes Yes Yes Yes
  • a Mutually exclusive drugs in mixture give a parallel median-effect plot with respect to each drug alone

  • b Mutually nonexclusive drugs in mixture give a upwardly concave dose-effect curve with respect to each drug alone

  • c Hyperbolic dose-effect curve

  • d Sigmoidal dose-effect curve

  • e i1,2 = 1 – [(1 – i1)(1 – i2)] or (fu)1,2 = (fu)1 (fu)2 (see Webb, 1963)

  • f See Loewe (1957)

  • g see Eq. 16, which is the classic isobologram for mutually exclusive drugs. The conservative isobologram is for mutually nonexclusive drugs (Chou and Talalay, 1984). Since the early 1990s Chou has proposed using the mutually exclusive assumption as the universal standard for synergism and antagonism analysis, and, therefore, integrated the nonexclusive condition as an intrinsic contribution to the synergistic effect in the overall synergism and antagonism analysis. Thus, the isobologram and the Fa-CI plot become two sides of the same coin (see section II.C.6 or Chou, 1991, 1994, 1998): the Fa-CI plot is `effect-oriented', whereas the isobologram is `dose-oriented'