Effects of Drug Pretreatment on Antipyrine Levels in Blood and Tissues: An Example of Multiple Drug Interactions

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Abstract
The effect of drug pretreatment on plasma and tissue levels of antipyrine in rats was investigated. Rats received for 3 days i.p. injections of saline, phenobarbital (PHE), diphenylhydantoin (DPH), SKF-525 A, PHE plus SKF-525 A or PHE plus DPH, respectively. Antipyrine was administered i.p. exactly 1 h after the last pretreatment dose, and antipyrine concentrations in plasma, liver and brain weredetermined at regular intervals thereafter. Pretreatment with PHE enhanced the disappearance rate of antipyrine from blood and tissues, whereas pretreatment with DPH had an opposite effect. Pretreatment with SKF-525 A decreased the rate of antipyrine disappearance. In animals pretreated with a combination of drugs, the metabolism of antipyrine was altered, the net effect being that of a summation of the effect of each agent used in the pretreatment. The results demonstrate the need for care in evaluating the fate of a compound in the body when several drugs are administered simultaneously. In addition to changing the hepatic drug-metabolizing capacity, pretreatment with several drugs results in competition for hepatic drug metabolism and brain uptake.

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