Abstract
Distribution kinetics of 5-ethyl-substituted oxy-, N-alkyl-, and thiobarbiturates covering a range of partition coefficients of octanol/water (log P 1.6 to 4.1) were determined in rats. Concentration-time curves for plasma, adipose tissue, liver, and muscle after single iv administration were obtained using HPLC analysis. Pharmacokinetic parameters were calculated for plasma and tissues. A physiological pharmacokinetic model allowed the simulation and prediction of adipose tissue kinetics based on blood and plasma kinetics, adipose tissue/plasma distribution coefficient, volume and perfusion rate of adipose tissue. Adipose tissue storage was quantified with the adipose storage index (ASI). Including data of barbiturates from the literature, the correlation between ASI and log P was poor except for oxybarbiturates not substituted in N1. Within comparable log P ranges, ASI values increased from oxy- to N-alkylated to thiobarbiturates. Thus, even within the chemical class of barbiturates log P is not a sufficient criterion for adipose tissue storage. Rather, adipose tissue storage is influenced by individual functional groups.
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