Influence of nutritional status on the pharmacokinetics and pharmacodynamics of pentobarbital

The influence of dietary protein deficiency on the pharmacokinetics and pharmacodynamics of pentobarbital was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23% (control) or 5% (low) protein diet ad libitum. Following a single iv dose of 40 mg/kg sodium pentobarbital, the average mean residence time (MRT) was prolonged by 144% (2.3 +/- 0.2 to 5.6 +/- 1.5 hr, mean +/- SD) in the protein-deficient rats, whereas the mean total body clearance (CL) per kilogram of body weight decreased from 0.56 +/- 0.09 to 0.22 +/- 0.06 liter/hr/kg. As a result, the terminal disposition rate constant was decreased by approximately 60% (0.398 +/- 0.037 to 0.178 +/- 0.050 hr-1 when compared to rats on a normal protein diet. No significant differences were found in the two groups of rats with respect to the apparent steady state volume of distribution (Vss). In order to investigate the effect of nutritional status on the concentration-pharmacologic activity relationship, pentobarbital was infused iv at a constant rate of 0.55 mg/min until the animals lost their righting reflex (16 +/- 3 min and 8 +/- 1 min in control and protein-deficient animals, respectively). The total dose and concentration of pentobarbital in plasma were not significantly different between the two groups of animals. However, the concentrations of pentobarbital in plasma water (unbound) and brain were appreciably higher in the rats on a low protein diet. Thus, a diet low in protein appears to be associated with a decreased sensitivity of the central nervous system to the depressant effect of pentobarbital.