Hi all,
I am using several muscarinic receptor antagonists at comparable doses in my study, and I wish to compare their efficacies across experiments.
To add more, experiments are performed in vivo where we measure the effects of receptor antagonism in the brain on motor output. In each experiment, only one antagonist is used. I have looked up the literature on this topic and have found the IC50 values of all antagonists, but given the fact that IC50 depends on ligand/substrate concentration, can it even be used for efficacy comparison purposes in my project?
Any insight would be appreciated.
The IC50 represents the situation of in vitro experiments in which the drug concentration is constant during the course of the experiment. This is usually not true in vivo because drug absorption, distribution, metabolism and elimination (ADME) result in a time-varying drug concentration. Therefore, it is also necessary the study how the drug concentration varies in time after dosing in vivo (pharmacokinetics). You also need to develop an understanding of the relationship between the pharmacokinetics and the effect of the drug in vivo (pharmacodynamics).
Since different drugs are likely to have differences in their pharmacokinetic and/or pharmacodynamic properties, the IC50 alone is insufficient information to predict in vivo efficacy.
Adam B Shapiro Thank you! I only need the information about the efficacies as a discussion point for a paper. What about the inhibition constant (Ki)? Since that should be constant for all ligand concentrations?
The Ki is a constant for the ligand-receptor pair under a particular set of conditions. It is the equilibrium dissociation constant of the pair (also called the Kd).
In the simplest system, where the effect of the antagonist is directly measured (e.g. purified receptor, single ligand binding site), the relationship between the IC50 and the Ki depends on the setup of the assay used to measure the IC50. If the inhibitor has to compete with another ligand L, then the IC50 will be higher than the Ki, according to the equation IC50= Ki(1+[L]/Kd,L). If there is no other ligand in the assay, then the IC50 will equal the Ki.
The receptor concentration must be much lower than the antagonist IC50 for the above equation to be correct. Otherwise, the quadratic tight binding equation of Morrison should be used for the analysis of the inhibition data.
In a more complex system, such as when monitoring the effect of the receptor antagonist on the behavior of cells (e.g. cell death or secretion of something), such a simple analysis is probably not going to apply very well, and you will be limited to using the IC50 as a description. In some cases, particularly for covalent inhibitors, it is possible to relate the IC50 to % receptor occupancy with inhibitor experimentally.
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