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.
Xie
X
X
Department of Pharmacology, University of Berne, Switzerland.
Steiner
S H
SH
Bickel
M H
MH
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001569:Benzodiazepines; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002849:Chromatography, Gas; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D014018:Tissue Distribution
D014151:Anti-Anxiety Agents; D001569:Benzodiazepines