We have discovered a new type of drug-drug interaction where one substance increases the plasma protein binding of another drug. This increase is mediated by a large elevation in a nonprecipitatable plasma glycoprotein, probably Alpha1-acid glycoprotein (AGP). AGP is an important binding protein for many basic lipophilic drugs so that major alterations in its concentrations may have important consequences in terms of the disposition and action of many drugs. The three substances we have already shown capable of inducing the plasma binding of propanolol, phenobarbital, phenytoin, and Arochlor 1254, are all known to be inducers of drug metabolism. We propose to study a variety of other inducers of enzyme activity to establish what types of drugs and chemicals can affect AGP production. The kinetic time course of the change in AGP concentrations could not be explained by any existing theory of induction. We have developed a new kinetic theory of enzyme induction which takes into account the pharmacokinetics of the inducing agent. By measuring the plasma concentrations of each inducing drug we can evaluate the applicability of this new model for a wide variety of agents. Because the three substances which induce AGP are also inducers of drug metabolism, we propose to evaluate the parallelism between induction of drug metabolism and induction of plasma protein binding. For this purpose, we will measure pharmacokinetic markers of drug metabolism as a function of time during the period of induction and after the inducing stimulus is withdrawn. These data along with parallel experiments which measure propanolol plasma binding and AGP concentration will be compared in terms of the time courses of the two types of induction and the Km's for the induction of each process. We will also evaluate whether phenobarbital-type induction and/or beta-naphthoflavone-type induction is related to the induction of plasma proteins.
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