Effects of individual variations in drug elimination kinetics for production of pentobarbital physical dependence.

Many studies have suggested the importance of the rate of drug elimination in the development of pharmacodynamic tolerance and physical dependence to sedative-hypnotics. However, these studies usually compared drugs whose pharmacokinetic properties differed widely, e.g., short- vs. long-acting barbiturates. Accordingly, we investigated the relationship between individual variations in the rate of elimination of a single drug, pentobarbital, and the severity of physical dependence which developed during chronic pentobarbital administration. Animals were treated with Na pentobarbital according to the "maximally tolerable" dosing schedule described previously, twice a day for 35 days, and abruptly withdrawn. The relationship between chronic treatment variables (doses and blood concentrations of pentobarbital, peak and residual central nervous system depression scores), elimination half-lives and withdrawal intensity were explored. Withdrawal intensity was evaluated as overall withdrawal intensity ratings, the number and types of spontaneous withdrawal convulsions and lethality. Individual variations in the drug elimination half-lives related significantly to the severity of physical dependence produced by pentobarbital: the longer half-life, the more intense the production of physical dependence by pentobarbital.