Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 1999 May;127(1):227-35.
doi: 10.1038/sj.bjp.0702499.

Rate of Change of Blood Concentrations Is a Major Determinant of the Pharmacodynamics of Midazolam in Rats

Affiliations
Free PMC article

Rate of Change of Blood Concentrations Is a Major Determinant of the Pharmacodynamics of Midazolam in Rats

A Cleton et al. Br J Pharmacol. .
Free PMC article

Abstract

The objective of this investigation was to characterize quantitatively the influence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic modelling approach. Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml(-1) was obtained over different time intervals of 16 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml(-1) min(-1). In one group of rats the midazolam concentration was immediately brought to 80 ng ml(-1) and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG effect in conjunction with the decline of midazolam concentrations. The increase in beta activity (11.5-30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG effect could be described by the sigmoidal Emax model. After placebo, the values of the pharmacodynamic parameter estimates were Emax = 82+/-5 microV, EC50,u = 6.4+/-0.8 ng ml(-1) and Hill factor = 1.4+/-0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC50,u was observed with a maximum of 21+/-5.0 ng ml(-1) at a rate of change of 0.46 ng ml(-1) min(-1); lower values of EC50,u were observed at both higher and lower rates. The findings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.

Figures

Figure 1
Figure 1
Predicted concentration versus time profiles during the first 4–6 h of the experiment. The arrow marks the start of the midazolam bolus infusion at the end of the pretreatment (10 mg kg−1, 5 min). The linear increase in rate of rise in blood concentrations during the first 6, 4, 3, 2, 1.5, 1 h, are represented by the dashed lines, whereas the closed line represents the 4 h treatment at the EC50 concentration of 150 ng ml−1.
Figure 2
Figure 2
Blood concentration (A) and EEG effect (B) time profiles for a typical rat which was expected to receive a rate of rise of increase of midazolam concentration from 0–150 ng ml−1 in 4 h and a intravenous bolus dose of 10 mg kg−1 midazolam in 5 min. A bi-exponentional equation was fitted to the midazolam concentration data after the administration of the bolus dose. (N.B. The first 4 h of the infusion are plotted on a linear scale, whereas the concentrations after administering the bolus dose are plotted on a semi-logarithmic scale).
Figure 3
Figure 3
Observed midazolam blood concentration versus time profiles upon exponential infusion upon different administration rates. The straight lines represent the fits on basis of linear regression analysis.
Figure 4
Figure 4
Midazolam concentration–EEG effect relationship for two typical rats which received different rates of rise of increase in midazolam concentration from 0–150 ng ml−1 followed by a bolus dose of 10 mg kg−1 midazolam in 5 min. The solid line represents the best fit to the actual data points according to the sigmoidal Emax model.
Figure 5
Figure 5
Relationship between the individual EC50,u values and the rate of increase in midazolam concentration. The shaded area in the figure presents the 95% confidence interval of the EC50,u values in the placebo group. The curve was not fitted to the data but drawn to show the bell-shape form (n=37).
Figure 6
Figure 6
Plot of the intrinsic efficacy (Emax) versus the rate of increase in midazolam concentration for each individual animal. The shaded area in the figure presents the 95% confidence interval of the Emax values in the placebo group. The solid line represents the regression line: Y=50.6+29.8 (dC/dt); (r2=0.327, n=37).

Similar articles

See all similar articles

Cited by 4 articles

Publication types

LinkOut - more resources

Feedback