Kinetics of distribution and adipose tissue storage as a function of lipophilicity and chemical structure. II. Benzodiazepines.

Distribution kinetics of flurazepam, medazepam, prazepam, and clobazam were determined in rats. Concentration-time curves of unchanged drugs and non-polar metabolites in plasma, adipose tissue, liver, brain, and muscle after a single iv administration were obtained using GLC/electron capture detector analysis. Pharmacokinetic parameters were calculated for plasma and tissues. Adipose tissue storage was quantified with the adipose storage index (ASI). Including data of benzodiazepines from the literature, a correlation between ASI and log P (over a range 1.6-3.8) was nonexistent and the influence of individual functional groups was not easily discernible. However, benzodiazepines with a pKa (base) within the range 1.6-6.2 were stored in adipose tissue (ASI greater than 1), whereas those with pKa greater than 7 were not (ASI less than 1). Since many other basic lipophilic drugs with pKa greater than 7 are not stored in adipose tissue, and this is likely due to lysosomal trapping in lean tissues, which requires a pKa value above 7, it is suggested that within the series of benzodiazepines, adipose tissue storage is mainly influenced by the basicity of the drugs.