Pharmacodynamics Of Midazolam Research Articles

Influence of Acetaminophen on Pharmacokinetics and Pharmacodynamics of Midazolam in Healthy Volunteers

Background: Midazolam and acetaminophen are often co-administered in anesthesia practice. Both are metabolized by CYP 3A4 enzyme in the liver, and hence compete for the enzyme sites. This might lead to reduced metabolic breakdown and enhanced pharmacodynamic effects of midazolam in the presence of acetaminophen. Methods: The present study was undertaken to test this hypothesis. After IRB approval from Mount Sinai Medical Center, 15 healthy volunteers were used for 2 tests. For the first test, they were randomly assigned to receive oral doses of either midazolam 0.3 mg/kg in cherry syrup (Protocol A), or midazolam 0.3 mg/kg plus cherry flavored acetaminophen 15 mg/kg (Protocol B). At set intervals from 0 to 480 min, the blood levels of midazolam and the subjects pulse rate, mean arterial pressure, respiratory rate, BIS index, and OAA/S scores were determined. After 2 weeks, the same subjects underwent the second test; they received the other medication protocol. Results: Acetaminophen slightly, but not significantly, increased the half life of blood midazolam, and the depressive effects of midazolam on the clinical signs of the subjects. Conclusion: These results lead us to conclude that there is no need to reduce the doses of midazolam when used in combination with acetaminophen.

The combined effects of midazolam and propofol sedation on muscle power

We performed a randomised, crossover study to investigate the effects of intravenous sedation on grip strength and bite force. Twenty male volunteers received a bolus intravenous injection of midazolam (0.02 mg.kg(-1)) together with a 30-min propofol infusion designed to achieve an effect-site concentration of 1.0 μg.ml(-1). Observed variables included bispectral index, observer's assessment of alertness/sedation, correct answer rate of Stroop colour-word test, grip strength and bite force. Grip strength decreased from a median (IQR [range]) of 483 (443-517 [380-586]) N to 358 (280-405 [108-580]) N (p < 0.001) during sedation and recovered following flumazenil administration, while bite force increased from 818 (593-1026 [405-1406]) N to 1377 (1243-1585 [836-2357]) N (p < 0.001) during sedation. Although bite force gradually returned to baseline following flumazenil administration, it remained increased throughout the experimental period. We conclude that bite force increased during intravenous sedation and that this may have clinical implications.

Pharmacokinetics and pharmacodynamics of midazolam after intravenous and intramuscular administration in alpacas

To determine pharmacokinetic and pharmacodynamic properties of midazolam after IV and IM administration in alpacas. 6 healthy alpacas. Midazolam (0.5 mg/kg) was administered IV or IM in a randomized crossover design. Twelve hours prior to administration, catheters were placed in 1 (IM trial) or both (IV trial) jugular veins for drug administration and blood sample collection for determination of serum midazolam concentrations. Blood samples were obtained at intervals up to 24 hours after IM and IV administration. Midazolam concentrations were determined by use of tandem liquid chromatography-mass spectrometry. Maximum concentrations after IV administration (median, 1,394 ng/mL [range, 1,150 to 1,503 ng/mL]) and IM administration (411 ng/mL [217 to 675 ng/mL]) were measured at 3 minutes and at 5 to 30 minutes, respectively. Distribution half-life was 18.7 minutes (13 to 47 minutes) after IV administration and 41 minutes (30 to 80 minutes) after IM administration. Elimination half-life was 98 minutes (67 to 373 minutes) and 234 minutes (103 to 320 minutes) after IV and IM administration, respectively. Total clearance after IV administration was 11.3 mL/min/kg (6.7 to 13.9 mL/min/kg), and steady-state volume of distribution was 525 mL/kg (446 to 798 mL/kg). Bioavailability of midazolam after IM administration was 92%. Peak onset of sedation occurred at 0.4 minutes (IV) and 15 minutes (IM). Sedation was significantly greater after IV administration. Midazolam was well absorbed after IM administration, had a short duration of action, and induced moderate levels of sedation in alpacas.

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers.

Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μM and 0.6 μM, respectively). The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes.

Growing up with Midazolam in the Neonatal and Pediatric Intensive Care

A variety of developmental changes is of influence on the pharmacokinetics and pharmacodynamics of midazolam in neonatal and pediatric intensive care patients. However, dosing regimens in children are based upon rather empirical extrapolations from the dosing regimens in adults. Based on current available studies it appears that with the rising of age, the pharmacokinetics of intravenously administered midazolam alter, resulting in a shorter half-life due to a higher hepatic clearance in older children as compared to newborn. Also, with the rising of age, the pharmacodynamics of intravenously administered midazolam may alter due to a decrease in density of receptors, possibly leading to a decreased clinical response. These findings implicate opposite effects and it is uncertain which of these effects are predominant. In conclusion, there is a large interindividual variability in the response to midazolam in children, which may be caused by differences in pharmacokinetics and pharmacodynamics. Both are subject to considerable developmental changes. It remains remarkable that high-quality evidence to support the use of midazolam for continuous sedation in the neonatal and pediatric intensive care setting is lacking.

Pharmacokinetics and pharmacodynamics of low doses of midazolam administered intravenously and orally to healthy volunteers

1. Midazolam, a short-acting benzodiazepine, has been considered a probe for estimating hepatic and intestinal cytochrome P450 (CYP) 3A activity in humans. The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of midazolam administered intravenously (i.v.) and orally (p.o.) at relatively low doses to healthy volunteers. 2. The present study was an open-label, single-sequence trial in three phases distinguished by differing doses of midazolam. Plasma concentrations of midazolam and its metabolites, as well as pharmacodynamic parameters, were measured simultaneously after administration of 5, 15 and 30 microg/kg, i.v., midazolam and 15, 50 and 100 microg/kg, p.o., midazolam. 3. The area under the concentration-time curve (AUC) of midazolam was significantly correlated with dose after both i.v. and oral administration (both P < 0.001). The AUC(0-6) of midazolam after oral administration was also well correlated with the area under the effect curve for peak saccadic velocity (PSV; P < 0.018), postural sway area (PSA; P < 0.069) and mental sedation as measured on a visual analogue scale (VAS; P < 0.054), but not for critical flicker fusion. 4. The present study has shown that the pharmacokinetics of midazolam at relatively low doses are linear for both intravenous and oral dosing regimens. In addition, PSV, PSA and VAS may be useful for the simultaneous evaluation of the pharmacokinetics and pharmacodynamics of midazolam at subtherapeutic doses.

Effect of intravenous flumazenil on oral midazolam pharmacokinetics and pharmacodynamics for use as a cytochrome P450 3A probe

Phenotyping intestinal and hepatic cytochrome P450 (CYP) 3A activity with oral midazolam can be limited by midazolam-induced central nervous system (CNS) side effects. Determining methods to minimize CNS side effects optimizes use of midazolam as a CYP3A probe. The objective of this study was to determine the effect of intravenous (i.v.) flumazenil on midazolam apparent oral clearance (a surrogate marker of CYP3A activity). Midazolam pharmacodynamics were also evaluated. This was a randomized, double-blind, placebo-controlled, single-dose, two-way crossover study. 16 healthy volunteers (8 women) were concomitantly administered i.v. flumazenil 0.005 mg/kg or i.v. placebo and oral midazolam 0.075 mg/kg. Blood samples were obtained to determine midazolam and flumazenil plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMR) and 90% confidence intervals (90% CI). Baseline and post dose digit symbol substitution tests (DSST), Groton maze learning tests (GMLT), and Stanford sleepiness scales (SSS) were conducted. Apparent oral clearance was 2,030 +/- 651 and 1,939 +/- 658 ml/min for the midazolam plus flumazenil and midazolam plus placebo groups. Equivalence in midazolam apparent oral clearance was observed (%GMR flumazenil/placebo, 90% CI 104.8, 94 - 116.6%). Flumazenil partially attenuated oral midazolam pharmacodynamics. Exploratory post hoc analyses revealed that midazolam exposure was 1.9-fold higher in men compared to women. i.v. flumazenil can be used in conjunction with oral midazolam for CYP3A phenotyping.

Effects of ursodeoxycholic acid on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam in healthy volunteers

Animal and in vitro studies suggest that ursodeoxycholic acid (UDCA) can induce cytochrome P450 3A (CYP3A) expression and enhance its activities. On the other hand, Becquemont et al. demonstrated that UDCA had no influence on intestinal CYP3A activities. The aim of this study was to investigate the effects of UDCA on the intestinal and hepatic CYP3A activities by administration of midazolam (MDZ), as a specific probe for CYP3A activity, in humans. This was a randomized, open-label, crossover study with two phases in 14 healthy volunteers. The volunteers received UDCA (300 mg/day) or placebo orally for 9 days. The pharmacokinetics and pharmacodynamics of intravenous MDZ (5 microg/kg) and oral MDZ (15 microg/kg) were assessed on days 8 and 9, respectively. The pharmacodynamics of MDZ was estimated by measuring peak saccadic velocity, postural away length, critical fusion flicker frequency, and visual analogue scale. UDCA did not affect the pharmacokinetic and pharmacodynamic parameters of intravenous and oral MDZ administrations. Our study suggests that the clinical dosage of UDCA could not affect both hepatic and intestinal CYP3A activities and that the drug interaction between UDCA and substrates for CYP3A is unlikely in humans.

Pharmacokinetics and Pharmacodynamics of Midazolam and Metabolites in Nonventilated Infants after Craniofacial Surgery

Because information on the optimal dose of midazolam for sedation of nonventilated infants after major surgery is scant, a population pharmacokinetic and pharmacodynamic model is developed for this specific group. Twenty-four of the 53 evaluated infants (aged 3-24 months) admitted to the Pediatric Surgery Intensive Care Unit, who required sedation judged necessary on the basis of the COMFORT-Behavior score and were randomly assigned to receive midazolam, were included in the analysis. Bispectral Index values were recorded concordantly. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). For midazolam, total clearance was 0.157 l/min, central volume was 3.8 l, peripheral volume was 30.2 l, and intercompartmental clearance was 0.30 l/min. Assuming 60% conversion of midazolam to 1-OH-midazolam, the volume of distribution for 1-OH-midazolam and 1-OH-midazolamglucuronide was 6.7 and 1.7 l, and clearance was 0.21 and 0.047 l/min, respectively. Depth of sedation using COMFORT-Behavior could adequately be described by a baseline, postanesthesia effect (Emax model) and midazolam effect (Emax model).The midazolam concentration at half maximum effect was 0.58 mum with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized. In nonventilated infants after major surgery, midazolam clearance is two to five times higher than in ventilated children. From the model presented, the recommended initial dosage is a loading dose of 1 mg followed by a continuous infusion of 0.5 mg/h during the night for a COMFORT-Behavior of 12-14 in infants aged 1 yr. Large interindividual variability warrants individual titration of midazolam in these children.

Pharmacodynamics of Midazolam in Pediatric Intensive Care Patients

The aim of the study was to study a possible pharmacokinetic-pharmacodynamic (PK-PD) relationship for midazolam in pediatric intensive care patients and to determine how adequate sedation could be reached using the COMFORT scale as sedation scale. Twenty-one pediatric intensive care patients (2 days to 17 years) received a midazolam infusion (0.05-0.4 mg/kg/h, 3.8 hours to 25 days). Sedation levels were determined using the COMFORT scale as well as plasma concentrations of midazolam and metabolites. An evident PK-PD relationship was not found. In 20 of the 21 patients midazolam dosing could be effectively titrated to the desired level of sedation, assessed by the COMFORT scale. Based on our findings that there is no relationship between pharmacokinetic parameters and pharmacodynamic outcome, we recommend that midazolam dosing should be titrated according to the desired clinical effect in combination with a validated assessment instrument, eg, the COMFORT scale.

Effect of Licorice (Radix Glycyrrhizae) Water Extract on the Pharmacokinetics and the Pharmacodynamics of Midazolam in Healthy Subjects

Effect of Licorice (Radix Glycyrrhizae) Water Extract on the Pharmacokinetics and the Pharmacodynamics of Midazolam in Healthy Subjects

Useful Information about the pharmacokinetics and Pharmacodynamics of Midazolam and Lorazepam

VA Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, California. barrj@leland.stanford.eduIn Reply:—We appreciate the points raised by Dr. Deem. Our manuscript addresses the differences in infusion duration. 1To briefly recapitulate: this was a double-blind, randomized study. Occasionally randomization fails to divide patient covariates evenly between groups. The smaller the study, and the more covariates considered, the more likely it is that not all covariates will be evenly divided between groups. Since randomization failed to provide similar durations of infusions, we used a model-based approach to draw clinical inference from the fundamental PK/PD characteristics. Those inferences support our conclusions. The half-lives reported for midazolam (10 h) and lorazepam (16 h) in our manuscript are consistent with the published PK of midazolam 2–7and lorazepam. 7–12As explained in the manuscript, fentanyl was administered by target-controlled infusion, set to 1.5 ng/ml. Because this was a randomized study, the concept of “standardizing analgesic regimens between groups” is irrelevant. There was no difference in the fentanyl administered to the two groups, nor in the “success of the associated analgesic regimen.”Swart et al . reported that 5 of 6 patients with delayed midazolam elimination had been treated with erythromycin for more than 2 days. 7Obviously such patients should be treated with drugs not metabolized by CYP 3A4, such as lorazepam. Absent those patients, the variability in midazolam and lorazepam reported by Swart was similar to what we observed in our patients, none of who received erythromycin. We cannot explain why Swart et al . were unable to achieve the desired level of sedation with midazolam, despite average infusions rates of 16 mg/hr. In our experience, adequate sedation, including complete unconsciousness, can be achieved with either drug, and at far lower doses of midazolam than reported by Swart.As Dr. Deem notes, Swart et al report a 15-fold difference in infusion rates between midazolam and lorazepam. This is much higher than in our study or in other published comparisons of midazolam and lorazepam in the intensive care unit. 13,14Of note, the dosing differences for midazolam and lorazepam reported by Swart et al . correspond exactly with the concentration differences of drugs in their syringes: 0.33 mg/ml of lorazepam versus 5 mg/ml of midazolam. Swart et al . titrated to deep levels of sedation, where drug effect is difficult to assess precisely. In this study design, lack of precise titration to drug effect would be expected to produce a 15-fold potency difference by default. We believe this is the most likely explanation for their anomalous results.Our manuscript documents that both midazolam and lorazepam are effective drugs for intensive care unit sedation, and provides guidelines in administering them to achieve comparable results. We did not address which drug was cheaper in the long run, which is a complex question involving far more than drug acquisition costs.

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.

Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol.

The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ1 receptor subtype selective agonist zolpidem have been determined in the rat in vivo, using an integrated pharmacokinetic-pharmacodynamic approach. Ethanol was administered as a constant rate infusion resulting in constant plasma concentrations of 0.5 g/l. The pharmacokinetics and pharmacodynamics of midazolam, bretazenil, and zolpidem were determined following an intravenous infusion of 5.0, 2.5, and 18 mg/kg respectively. The amplitude in the 11.5-30 Hz frequency band of the EEG was used as measure of the pharmacological effect. For each of the benzodiazepines the concentration-EEG effect relationship could be described by the sigmoid Emax pharmacodynamic model. Significant differences in both EC50 and Emax were observed. The values of the EC50 were 76 +/- 11, 12 +/- 3, and 512 +/- 116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the Emax were 113 +/- 9, 44 +/- 3, and 175 +/- 10 microV/s. In the presence of ethanol the values of the EC50 of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for Emax and Hill-factor were unchanged Due to a large interindividual variability no significant change in EC50 was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant KPD for all three drugs, indicating that changes in EC50 can be explained entirely by a change in the apparent affinity constant KPD without concomitant changes in the efficacy parameter ePD and the stimulus-effect relationship. The findings of this study show that the pharmacodynamic interactions with a low dose of ethanol in vivo are qualitatively and quantitatively similar for benzodiazepine receptor full agonists, partial agonists, and benzodiazepine BZ1 receptor subtype selective agonists. This interaction can be explained entirely by a change in the affinity of the biological system for each benzodiazepine.

In vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheep.

The cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepam were examined in chronically instrumented sheep via measurements of their arterio-venous concentration difference across the brain during and after 2-min i.v. infusions. Diazepam (30 mg) or midazolam (10 mg) were administered on 5 separate occasions to 4 sheep. For both drugs, rapid cerebral uptake occurred during the infusion, which quickly turned to elution in the postinfusion period. However, this process was more rapid for midazolam than diazepam. The cerebral pharmacokinetics of both was better described by a kinetic model with slight membrane limitation rather than flow limitation. For diazepam, the estimated brain:plasma partition coefficient was 2.67, and the first and second compartments filled with half-lives of 2.2 and 0.5 min, respectively. For midazolam, these values were 0.27, 0.26 and 1.34 min, respectively. In a subset of sheep, pulmonary arterial-arterial gradients were too small to measure suggesting limited metabolism and small distribution volumes for both drugs in the lungs. Simultaneous dynamic measurements of cerebral blood flow and algesimetry lagged behind both the arterial and sagittal sinus blood concentrations. The changes in cerebral blood flow were best described by a previously published a dynamic model that incorporated long half-lives for drug dissociation from the benzodiazepine receptor (13.3 and 5.5 min for midazolam and diazepam, respectively). Effect compartment modeling of the cerebral blood flow data showed apparent effect compartment half-lives (t1/2,keo) that were longer than the half-lives of cerebral equilibration.

Mechanism-based modeling of functional adaptation upon chronic treatment with midazolam.

A mechanism-based model is applied to analyse adaptive changes in the pharmacodynamics of benzodiazepines upon chronic treatment in rats. The pharmacodynamics of midazolam was studied in rats which received a constant rate infusion of the drug for 14 days, resulting in a steady-state concentration of 102 +/- 8 ng x ml(-1). Vehicle treated rats were used as controls. Concentration-EEG effect data were analysed on basis of the operational model of agonism. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation. The relationship between midazolam concentration and EEG effect was non-linear. In midazolam pre-treated rats the maximum EEG effect was reduced by 51 +/- 23 microV from the original value of 109 +/-15 microV in vehicle treated group. Analysis of this change on basis of the operational model of agonism showed that it can be explained by a change in the parameter tissue maximum (Em) rather than efficacy (tau). In the in vitro studies no changes in density, affinity or functionality of the benzodiazepine receptor were observed. It is concluded that the observed changes in the concentration-EEG effect relationship of midazolam upon chronic treatment are unrelated to changes in benzodiazepine receptor function.

The effect of age on the pharmacokinetics and pharmacodynamics of midazolam.

We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect. Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device. Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli). An EEG was recorded to quantitate the hypnotic effect, relating the median frequency of the power spectrum to the plasma level by a sigmoid Emax model, including an effect compartment. Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model. The total doses needed to reach the defined end points were 71+/-9 mg and 35+/-6 mg for the younger and elderly subjects, respectively (P < .001). Pharmacokinetic parameters were similar in both groups (clearance, 399+/-91 and 388+/-97 mL/min; steady-state volume of distribution, 85+/-22 and 104 +/-11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522+/-236 ng/mL; elderly subjects, 223+/-56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis. We found much interindividual variability in the plasma concentrations necessary to achieve the clinical end points, regardless of age. These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats.

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.

Mechanism-based modeling of adaptive changes in the pharmacodynamics of midazolam in the kindling model of epilepsy.

A mechanism-based model is proposed for the analysis of adaptive changes in the pharmacodynamics of benzodiazepines in vivo. The pharmacodynamics of midazolam was studied in the kindling model of experimental epilepsy. Concentration-EEG effect data from kindled rats and their controls were fitted to the operational model of agonism. A stepwise procedure was used, allowing changes in the parameters efficacy (tau) and tissue maximum (Em) either separately or in combination. The results were compared to data obtained in vitro in a brain synaptoneurosomal preparation. The relationship between midazolam concentration and EEG effect was non-linear. In kindled rats the maximum EEG effect was reduced by 27+/-8.3 microV from the original value of 94+/-4.4 microV. Analysis on the basis of the operational model of agonism showed that this decrease could be explained by a difference in the parameter system maximum (Em) rather than efficacy (tau). In the in vitro receptor binding assay no changes in density, affinity or functionality of the benzodiazepine receptor were observed, consistent with the lack of a change in efficacy (tau). The operational model of agonism provides a mechanistic basis to characterise adaptive changes in the pharmacodynamics of midazolam.

Effects of glucocorticoids on pharmacokinetics and pharmacodynamics of midazolam in rats

We investigated the effect of dexamethasone (80 mg kg per day for 2 days) and prednisolone (600 mg kg per day for 2 days, equivalent to dexamethasone for glucocorticoid (GC) potency) on both pharmacokinetics and pharmacodynamics of midazolam (MDZ), a substrate for cytochrome P450 (CYP) 3A, in 8-week-old male Sprague-Dawley rats. Animals received a single injection of MDZ (pharmacokinetic study, 10 mg kg ; pharmacodynamic study, 55.5 mg kg ) in the tail vein 24 h after the last dose of GC or placebo. The elimination half-life (t 1 2 ) and the area under the concentration-time curve of MDZ were significantly reduced by pretreatment with dexamethasone to 58.9% and 44.7% of the control value, respectively, and the clearance of MDZ was significantly increased by dexamethasone. Similar changes observed by prednisolone pretreatment did not reach significance. The t 1 2 of the dexamethasone pretreatment group (14.4 ± 0.7 min) was significantly shorter than that of the prednisolone group (20.9 ± 1.5 min). The amount of CYP3A2 protein and the activity of erythromycin N-demethylase were significantly increased by dexamethasone and prednisolone pretreatments, but dexamethasone showed a greater effect than prednisolone. Sleeping time was significantly shortened by dexamethasone and prednisolone pretreatment to 38.7% and 57.1% of control value, respectively. The current study demonstrates that the anesthetic effect of MDZ would be reduced in patients treated with dexamethasone or prednisolone, and that the CYP3A induction was greater by dexamethasone than by prednisolone, implying that the potency of CYP3A induction may differ among GCs even when GC activity is the same.