title: Relevance of arteriovenous concentration differences in pharmacokinetic-pharmacodynamic modeling of midazolam.
abstract: In the present investigation, the extent of arteriovenous concentration differences of midazolam in rats was quantified, and the consequences of these differences on the pharmacodynamic estimates were determined. The arterial concentration-effect relationships where analyzed by a traditional-effect compartment model that characterizes the delay between blood and the effect site with the rate constant k(eo). Venous concentration-effect relationships where analyzed according to the traditional model and an extended-effect compartment model that, by incorporating an additional rate constant k(vo), can characterize the delay between the arterial and venous sampling site. Significant hysteresis was observed in the arterial but not the venous concentration-effect relationships. Rate constants for k(eo), k(vo) and terminal half-life were (mean +/- S.E.M.) 0.32 +/- 0.062, 0.093 +/- 0.013 and 0.0217 +/- 0.0008 min-1, respectively, indicating the existence of significant arteriovenous concentration differences. Pharmacodynamic estimates as determined on basis of the arterial concentrations and the traditional-effect compartment model were EC50 = 104 +/- 1 ng/ml, Emax = 151 +/- 4 microV/sec and gamma = 0.83 +/- 0.06. Analysis of the venous concentration-effect relationships on basis of the traditional- or extended-effect compartment model led to similar pharmacodynamic estimates, indicating that the observed arteriovenous concentration differences did not result in biased pharmacodynamic estimates. This is due to the fact that the effect relevant elimination rate constant of midazolam is relatively small compared with its k(eo). The observed results are consistent with earlier reports based on computer simulations.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Tuk
authors.forename: V M
authors.initials: VM
authors.lastname: Herben
authors.forename: J W
authors.initials: JW
authors.lastname: Mandema
authors.forename: M
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001158:Arteries; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014680:Veins
chemical_list: D014151:Anti-Anxiety Agents; D008874:Midazolam