Structure-pharmacokinetic relationships among the barbiturates in the rat

The pharmacokinetics of a congeneric series of barbituric acids were determined after i.v. administration of individual barbiturates or multicomponent barbiturate mixtures to chronically cannulated male rats. The concentration of barbiturate in plasma and urine was determined using reversed-phase high-performance liquid chromatography. A biexponential equation adequately fitted the plasma-concentration time data. The volume of distribution remained relatively constant within the series. Binding to plasma proteins varied enormously, increasing with lipophilicity. Accordingly, the volume of distribution based on unbound drug also increased with lipophilicity, reflecting a corresponding greater tissue affinity. Total clearance formed a relatively complex nonlinear relationship with lipophilicity. Although the affinity of the barbiturates for erythrocytes increased with lipophilicity, the relationship between total blood clearance and lipophilicity offered no simplification. Renal clearance, the minor route of elimination for the majority of the homologs, decreased with increasing lipophilicity, due to increased tubular reabsorption, whereas nonrenal (hepatic) clearance produced a nonlinear relationship with lipophilicity similar in form to that of total clearance. The nonlinearity of the hepatic clearance within the series was explained by a hepatic blood flow limitation, for the highest homologs, and by the stereochemistry of position 5 on the barbituric acid ring, for the lowest homologs.