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 were analyzed by a traditional-effect compartment model that characterizes the delay between blood and the effect site with the rate constantkeo. Venous concentration-effect relationships where analyzed according to the traditional model and an extended-effect compartment model that, by incorporating an additional rate constant kvo, 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 keo,kvo 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 μV/sec and γ = 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 keo. The observed results are consistent with earlier reports based on computer simulations.
Footnotes
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Send reprint requests to: Meindert Danhof, Ph.D., Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, University of Leiden, Sylvius Laboratory, P.O. Box 9503, 2300 RA Leiden, The Netherlands. E-mail: m.danhof{at}lacdr.leidenuniv.nl
- Abbreviations:
- A
- intercept of the plasmaconcentrationvs. time profile
- α
- first-order rate constant of the plasmaconcentration vs. time profile
- keo
- first-order rate constant for the distribution between arterial blood and the hypothetical effect compartment
- kvo
- first-order rate constant for the distribution between arterial and venous blood
- E0
- base-line effect value
- Emax
- maximal effect
- EC50
- concentration at half-maximal effect
- γ
- constant expressing the sigmoidicity of the concentration-effect relationship
- EEG
- electroencephography
- ς
- variance of parameter estimate
- Received May 8, 1997.
- Accepted September 16, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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