Effect compartment models—influence of *k*_{e0}. A simulation where a hypothetical drug is infused for 20 min, with resultant plasma concentrations (*C*_{p}) shown by blue. Each row shows the effect compartment concentrations (*C*_{eff}, orange) for a different effect compartment rate constant. Drug effect in arbitrary units (E, red) is related to the effect compartment concentrations by an *E*_{max} model with *E*_{max} = 1,000 and EC_{50} = 500. The left column shows the time course of *C*_{p}, *C*_{eff}, and *E*. The right column shows a hysteresis plot of *E* vs. *C*_{p} (blue) and *E* vs. *C*_{eff} (orange). (**a**) The time course of *C*_{eff} is similar to *C*_{p} for this value of *k*_{e0} and this study time scale. (**b**) As the maximum *C*_{p} is ~20 ng/ml, the *E*–*C*_{eff} relationship is essentially linear with a slope of 2 (1,000/500). The *E*–*C*_{p} relationship shows minimal hysteresis. (**c**) The time course of *C*_{eff} now lags behind *C*_{p}, and the peak *C*_{eff} occurs later than the peak *C*_{p} (although at equilibrium, *C*_{eff} = *C*_{p} by definition). (**d**) The *E*–*C*_{eff} relationship is unchanged, but the *E*–*C*_{p} relationship now shows hysteresis. The hysteresis is anticlockwise—the rise in concentration precedes the rise in effect. (**e**) The time course of *C*_{eff} is now substantially different to *C*_{p.} The transient peak in effect associated with the high *C*_{p} during the infusion is now absent. (**f**) The *E*–*C*_{p} relationship now shows hysteresis, with a complex shape dictated in part by the shape of the *C*_{p} time course.

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