Effect of Lipid Solubility and Dose on the Elimination of Barbiturates in Rabbits

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The elimination of seven barbiturates from plasma was studied in rabbits after intravenous administration at a dose of 20-80 mg/kg. The elimination rate constant, elimination half-life, and apparent volume of distribution of barbiturates did not depend on the dose. The area under the plasma concentration-time curve (AUC) of each barbiturate increased in proportion to the dose. Therefore, the distribution and elimination of barbiturates were considered to follow linear kinetics in rabbits. The elimination rate constant of barbiturates at a given dose was linearly related to the lipid solubility (measured as the partition coefficient between chloroform and pH 7.4 phosphate buffer). To investigate the effect of lipid solubility on the metabolism of barbiturates, the in vitro rate of metabolism in rabbit liver microsomes was determined. Only barbital (having low lipid solubility) was hardly metabolized during incubation for 60 min. A linear relationship was obtained for six barbiturates (not barbital) in a logarithmic plot of the in vitro metabolic rate constant vs. the partition coefficient. Furthermore, the in vivo elimination rate constant of the six barbiturates showed a good correlation with the in vitro metabolic rate constant in a logarithmic plot (r=0.9670). These results indicate that barbital was mainly eliminated by renal excretion, while other barbiturates were mainly eliminated metabolically in the liver, depending on their lipid solubilities.
公益社団法人日本薬学会の論文
1979-07-25

Effect of Lipid Solubility and Dose on the Elimination of Barbiturates in Rabbits

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