The purpose of this investigation was to determine the effect of
nephrotic syndrome (NS) on the pharmacodynamics of a
barbiturate. NS was induced in male rats by
puromycin aminonucleoside; it caused
hypoproteinemia, increased liver and kidney weight and elevated serum
creatinine and
urea nitrogen concentrations.
Serum albumin concentration decreased from 3.5% in controls to 0.90% in NS animals. The rats were infused i.v. with
heptabarbital, 1 mg/min, until they lost their righting reflex. The total dose (mean +/- S.D.) required by rats with NS, 40.2 +/- 4.2 mg/kg, was substantially lower than that required by normal animals (68.6 +/- 6.2 mg/kg, P less than .001).
Serum protein binding of
heptabarbital was reduced from 49% in controls to 26% in NS rats. However, the
drug concentration in cerebrospinal fluid (CSF) at the pharmacologic endpoint was not significantly different in controls and NS rats (18.9 +/- 1.5 vs. 18.3 +/- 1.4 mg/l). Serum, CSF and the brain contained appreciable concentrations of a metabolite of
heptabarbital. To determine if the metabolite contributes to the pharmacologic effect of the parent
drug, rats received an i.v. injection of 46, 60 or 100 mg/kg of
heptabarbital. Concentrations of
heptabarbital in CSF at return of righting reflex (which occurred after 15, 25 and 50 min, respectively) were independent of dose whereas metabolite concentrations increased with increasing dose. Thus, the metabolite of
heptabarbital in male rats is pharmacologically inactive.(ABSTRACT TRUNCATED AT 250 WORDS)