Strategy to assess the role of (inter)active metabolites in pharmacodynamic studies in-vivo: a model study with heptabarbital.

The purpose of this investigation was to develop a universal experimental strategy by which the role of (inter)active metabolites in in-vivo pharmacodynamic studies can be examined. Heptabarbital was chosen as a model drug and several pharmacokinetic variables which may affect in-vivo concentration-pharmacological response relationships were examined. Adult female rats received an i.v. infusion of the drug at one of three different rates (0.225-1.50 mg min-1) until the animals lost their righting reflex (after 11 +/- 1 to 88 +/- 8 min of infusion). The serum concentration of the drug at onset of loss of righting reflex (LRR) increased slightly with increasing infusion rate. The drug concentrations in brain tissue and cerebrospinal fluid (CSF), (mean +/- s.d.: 67 +/- 5 mg kg-1 and 24 +/- 4 mg L-1, respectively, for the lowest infusion rate) were not affected by the infusion rate. The possible contribution of (inter)active metabolites to the pharmacological response of heptabarbital was determined by administration of different i.v. bolus doses (14.1-22.5 mg) resulting in widely differing sleeping-times (7 +/- 3 to 119 +/- 20 min). The concentrations of heptabarbital in serum, brain tissue and CSF at offset of LRR (mean +/- s.d.: 77 +/- 8 mg L-1, 76 +/- 7 mg kg-1 and 29 +/- 5 mg L-1, respectively, for the highest dose) were not affected by the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)