title: In vivo modeling of the pharmacodynamic interaction between benzodiazepines which differ in intrinsic efficacy.
abstract: The pharmacokinetic and pharmacodynamic interactions between the benzodiazepine agonist midazolam, on one hand, and the partial agonist bretazenil and inverse agonist Ro 19-4603, on the other, were characterized in vivo in rats using effect parameters derived from quantitative EEG analysis. Male Wistar-derived rats received an i.v. infusion of 3 mg/kg bretazenil or 3 mg/kg Ro 19-4603 in 5 min during a steady-state infusion of midazolam at a rate of 2.8 mg/kg/hr. EEG signals were continuously measured and quantified by aperiodic EEG analysis and the change in amplitudes in the 11.5 to 30 Hz (beta) frequency band was used as measure of drug effect on the central nervous system. Frequent arterial blood samples were taken to determine the pharmacokinetics of the drugs. Both bretazenil and Ro 19-4603 did not influence the steady-state plasma concentrations of midazolam, but markedly antagonized the midazolam-induced increase in EEG effect measure to the extent of their own intrinsic maximal effects. The changes in EEG effect as a function of drug concentrations were described by a competitive interaction model, allowing the estimation of the pharmacodynamic parameters (means +/- S.E.) of the partial agonist, Emax = 15 +/- 5 microV/sec and EC50 = 19 +/- 5 ng/ml, and inverse agonist, Emax = -5.8 +/- 1.6 microV/sec and EC50 = 7.8 +/- 2.5 ng/ml. Similar values of the pharmacodynamic parameters were obtained after a single i.v. administration of these drugs, which provides evidence for the validity of the proposed interaction model.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: Mandema
authors.forename: M T
authors.initials: MT
authors.lastname: Kuck
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000818:Animals; D001381:Azepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D001381:Azepines; D001570:Benzodiazepinones; C056530:Ro 19-4603; C054626:bretazenil; D008874:Midazolam