Increased sensitivity to the anesthetic effect of phenobarbital in aging BN/BiRij rats

The purpose of this study was to determine the influence of age on the pharmacokinetic/pharmacodynamic relationship of phenobarbital in male BN/BiRij rats aged 4, 15, 26, 31 and 36 months. The pharmacokinetics were studied on basis of the plasma concentration vs. time profile and the excretion of phenobarbital and parahydroxyphenobarbital in urine and feces after an i.v. dose of 20 mg/kg. The pharmacodynamics were determined as the threshold dose and cerebrospinal fluid threshold concentration of phenobarbital for the onset of loss of righting reflex (as a measure of the anesthetic effect) during an i.v. infusion at a rate of 3 mg/min. The dose requirement for the anesthetic effect decreased with increasing age from 263 +/- 4 mg/kg (mean +/- S.E.M.) for the 4-month-old rats to 202 +/- 6 mg/kg for the 31-month-old rats. Only minor changes in the pharmacokinetic parameters, the metabolite profile and the distribution of phenobarbital between plasma (total and free), cerebrospinal fluid and brain tissue were observed. With respect to the pharmacodynamics, however, evidence for an increase in brain sensitivity was observed, as reflected in a decrease in the threshold cerebrospinal fluid concentration from 181 +/- 4 mg/l (mean +/- S.E.M.) at 4 months to 134 +/- 4 mg/l at 31 months. It is concluded that the decreased dose requirement of phenobarbital in elderly BN/BiRij rats is due to an increased brain sensitivity as a result of the aging process per se rather than detectable pathology.