Pharmacokinetics of simultaneously administered hexobarbital and heptabarbital in rats: an alternative approach to metabolic correlation studies.

The pharmacokinetics of hexobarbital and heptabarbital were studied after simultaneous oral administration to rats in order to correlate their rates of metabolism. Hexobarbital and heptabarbital were chosen for this purpose as model substrates because of their structural, pharmacokinetic as well as metabolic similarity. Blood concentrations were measured for 2 hr after administration by a capillary gas chromatographic method. In control rats (n = 8) elimination half-lives and intrinsic clearance values ranged between 13 to 28 min and 96 to 435 ml/min X kg for hexobarbital and between 8 to 21 min and 84 to 371 ml/min X kg for heptabarbital, respectively. A short-term pretreatment of rats (n = 7) with phenobarbital resulted in small but significant increases in the rates of metabolism of both barbiturates, whereas treatment of rats with 3-methylcholanthrene (n = 5) resulted in a reversed effect. Correlation of the elimination half-lives of the two drugs in all experiments was only weak (r = 0.70). The intrinsic clearance values reflecting enzyme activity in vivo, however, were found to correlate very strongly (r = 0.97). The results of this study suggest that an experimental approach, in which intraindividual differences are eliminated, appropriate kinetic parameters are studied and similarity of metabolic profiles are taken into consideration are preferable to the previously applied longitudinally designed correlation studies.