Effect of age, body composition, and lipid solubility on benzodiazepine tissue distribution in rats

Changes in body composition with age may alter tissue drug uptake and result in altered pharmacokinetics and pharmacodynamics. Four young, 4 middle-aged and 4 old Fischer-344 male rats were given a single intraperitoneal dose of alprazolam (2.5 mg/kg), diazepam (5 mg/kg) and triazolam (1.25 mg/kg) and sacrificed after 1 h. Diazepam, desmethyldiazepam, oxazepam, temazepam, alprazolam, and triazolam concentrations were determined in brain, kidney, liver, spleen, lung, heart, adrenal, muscle, fat and plasma by gas chromatography. Free fraction in plasma was determined by equilibrium dialysis. Drug uptake varied widely among tissues. Highest uptake ratios relative to free (unbound) drug in plasma were in adrenal (56-135), liver (35-116) and kidney (19-50). Free fraction in plasma varied from 0.13 for desmethyldiazepam to 0.30 for triazolam, and was unrelated to age. Tissue drug uptake relative to muscle, total plasma or free plasma concentration showed no significant variation with age or body habitus. In vivo fat uptake was highly correlated (R = 0.95) with in vitro octanol/buffer partition ratio. Muscle and fat were the largest quantitative drug storage sites, with total uptake explained by lipophilicity. Thus, age-related changes in body habitus and clearance do not alter tissue binding of benzodiazepines at distribution equilibrium.