1 The purpose of the present investigations was to determine the influence of increasing age on the pharmacokinetics and pharmacodynamics of midazolam in male BN/BiRij rats as an animal model of aging.2 Midazolam was administered intravenously at a dose of 2.5 mg kg-' and its pharmacokinetics were determined on the basis of plasma concentrations as measured by high performance liquid chromatography (h.p.l.c.). Pharmacodynamics were studied using the midazolam-induced changes in the electroencephalogram (EEG) as a measure of the pharmacological effect. Results were evaluated on the basis of stimultaneous pharmacokinetic-pharmacodynamic modelling. In an attempt to differentiate between the effects of aging and of concurrent disease, an extensive clinical biochemical/pathological examination was conducted in individual rats by an independent pathologist. 3 The pharmacokinetics of midazolam were best characterized on the basis of a two exponential model. In the 4-month-old rats the values of the clearance, volume of distribution and elimination half-life were 104 ± 13 ml min-' kg-' (mean ± s.e.mean), 3.4 ± 0.71 kg-1 and 30 + 3 min, respectively.With increasing age, no changes in the pharmacokinetics of midazolam were observed. 4 The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 ± 10%, 50 ± 6 lg 1' and 1.6 ± 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed. However, when diseased animals were excluded from the evaluation, a tendency towards a decrease in the midazolam concentration at half maximum effect to 25 ± 14 pg 1-1 was observed in the 36-month-old rats. 5 These findings suggest, that increasing age is associated with a tendency towards an increased brain sensitivity to midazolam, which is reflected in a parallel shift of the concentration vs. EEG effect relationship towards lower concentrations. However, it appears that factors other than age also contribute to interindividual variability in pharmacodynamics, considering the substantial interindividual variability within certain age groups.
In a previous study, an apparent age-related increase in brain sensitivity to the anesthetic effect of phenobarbital was observed in BN/BiRij rats. However, since this study was conducted according to a cross-sectional design, the observed change could, in principle, also have been the result of a cohort effect. The purpose of the present investigation was to exclude the role of such a cohort effect by adopting a "pseudo"-longitudinal study design. In this design 45 animals out of one cohort were reserved, and one subgroup was investigated at five ages (7, 14, 21, 29, and 34 months). A decrease in the anesthetic threshold dose of phenobarbital was found during aging, which appeared to be due mainly to an increase in the brain sensitivity. It is concluded that the previously observed increase in brain sensitivity is indeed the result of the aging process rather than a cohort effect.
The purpose of this study was to elucidate the structure of a metabolite of heptabarbitone, the occurrence of which was reported previously in a number of pharmacokinetic and pharmacodynamic modelling studies. By application of thermospray liquid chromatography (tandem) mass spectrometry, the identity of the metabolite was proposed to be 5-ethyl-5-(1',[3' or 6']-cycloheptadienyl)-barbituric acid. By measuring the ratios between the areas under the concentration time curves of the metabolite and heptabarbitone after administration of three different intravenous dosages of heptabarbitone, it was shown that the exposure to the metabolite is directly correlated with the exposure of heptabarbitone.
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