RT Journal Article
SR Electronic
T1 Kinetics of distribution and adipose tissue storage as a function of lipophilicity and chemical structure. II. Benzodiazepines.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 15
OP 19
VO 19
IS 1
A1 X Xie
A1 S H Steiner
A1 M H Bickel
YR 1991
UL http://dmd.aspetjournals.org/content/19/1/15.abstract
AB 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.