Vol. 284, Issue 1, 202-207, 1998

Relevance of Arteriovenous Concentration Differences in Pharmacokinetic-Pharmacodynamic Modeling of Midazolam

B. Tuk, V. M. M. Herben, J. W. Mandema and M. Danhof

Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, 2300 RA Leiden, The Netherlands (B.T., V.M.M.H., M.D.), and Stanford University School of Medicine, Department of Anesthesia, Stanford, California (J.W.M.)

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 were 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 min¹, 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, E_max = 151 ± 4 µV/sec and  = 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.