Kinetics of drug action in disease states. XXIX. Effects of experimental nephrotic syndrome on the pharmacodynamics of heptabarbital: Implications of severe hypoalbuminemia

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 < .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. It is concluded that NS has no effect on the pharmacodynamics of heptabarbital but that it causes pharmacokinetic changes mediated by the hypoalbuminemia and decreased drug-protein binding which lower substantially the infused dose required to produce the onset of a defined degree of central nervous system depression.