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02.12.2015

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The influence of low solubility drugs on their pharmacokinetics is variable, ranging from no effect to the factor of concentration dependence with the very dramatic and unexpected result of a two- to three-fold increase in apparent clearance of benzoic acid and salicylic acid after intravenous administration to rats to a decrease in apparent volume of distribution for phenobarbital (9.5 L/kg) and phenytoin (39 L/kg). These differences in the pharmacokinetics have been attributed to drug binding to serum proteins. One mechanism has been proposed in which the hydrophilic drug displaces the protein-bound drug from the protein, thereby reducing the drug concentration. A second mechanism has been proposed in which the protein-bound drug can displace other drugs bound to the protein. To further test these hypotheses, we examined the binding of the poorly soluble drugs (phenobarbital, phenytoin, thioridazine, and chlorpromazine) to rat serum proteins. We evaluated the binding of each drug at a low concentration (10 mumol/L), the biologically relevant concentration, and at the high concentration (50 mumol/L). The total concentration of protein-bound drug was measured at the end of the incubation period by precipitation of the proteins with trichloroacetic acid. The fraction of protein-bound drug at 10 mumol/L was approximately 1.0, 0.7, and 0.8 for phenobarbital, phenytoin, and thioridazine, respectively. The fraction of protein-bound drug at 50 mumol/L was approximately 1.0, 0.5, and 0.8, respectively. In addition, the effect of increasing the drug concentrations during the incubation period on drug binding was determined by measuring the rate of protein precipitation at the end of the incubation period. A linear relationship was found between the increase in concentration and the increase in the fraction of protein-bound drug. These results indicate that the mechanism of competition for binding to serum proteins appears to be a satur

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