Pharmacokinetic Parameters Of Midazolam Research Articles

Simvastatin Does Not Affect CYP3A Activity, Quantified by the Erythromycin Breath Test and Oral Midazolam Pharmacokinetics, in Healthy Male Subjects

Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.

Pharmacokinetics of midazolam and its main metabolite 1-hydroxymidazolam in intensive care patients.

The pharmacokinetics of midazolam and of its main metabolite, 1-hydroxymidazolam, were investigated in intensive care patients after intravenous bolus of 0.2 mg/kg followed by a 0.1 mg/kg/h intravenous infusion of midazolam over 2 hours. A wide interpatient variability of the main pharmacokinetic parameters of midazolam was found. The mean values of elimination half life and volume of distribution, 4.5 +/- 5.4 h and 1.7 +/- 0.7 l/kg respectively, were higher than those reported in healthy subjects. Total plasma clearance was significantly increased in patients taking drugs that induce hepatic metabolism. Significant concentrations of the unconjugated form of 1-hydroxymidazolam were recovered in plasma. The volume of distribution and the elimination half life of the metabolite were higher than those of the parent drug. These results show that 1-hydroxymidazolam might contribute to the pharmacodynamic effect of midazolam and consequently must be taken into account during pharmacokinetic and pharmacodynamic studies.

Early Pharmacokinetics of Midazolam

The influence of sampling site and sampling schedule on the early pharmacokinetics of a lipophilic drug, midazolam, was studied in 6 anaesthetised patients following an intravenous bolus injection of 0.05 mg/kg. Arterial and venous blood samples were drawn simultaneously over a period of 180 minutes. An extensive sampling procedure was used during the initial distribution phase; specifically, 12 arterial and 4 venous samples within the first 2 minutes. Midazolam concentrations were measured by high-performance liquid chromatography. Compared with peak venous concentrations, peak arterial concentrations were 2-fold greater and were reached 1 minute earlier. Although arterial concentrations exceeded corresponding venous concentrations for up to 90 minutes, a significant arteriovenous difference was observed during the first 2 minutes only. Consequently, noncompartmental pharmacokinetic parameters (mean residence time, volume of distribution at steady-state, total body clearance) obtained from arterial and venous values did not differ significantly. In addition, similar results were obtained for pharmacokinetic parameters using either the complete (continuous sampling over 2 minutes) or limited (assuming 1- and 2-minute samples only) arterial data set. It is concluded that both the sampling site and the sampling schedule altered the initial plasma concentration-time profile of midazolam. Although neither of these factors had a strong influence on the overall pharmacokinetic parameters of midazolam, their potential effect on the pharmacokinetic/pharmacodynamic relationship of midazolam during the onset phase should be considered.

Pharmacokinetics of midazolam in patients recovering from cardiac surgery.

The pharmacokinetics of midazolam has been studied in patients recovering from cardiac surgery, who required sedation for postoperative mechanical ventilation. Twelve males (mean age 64.5 years) with severe heart disease received an infusion of midazolam 15 mg.h-1 for 4 h, starting 1 to 3 h post surgery. Multiple blood samples were collected from each patient during the infusion and up to 48-93 h after it. The pharmacokinetic parameters of midazolam were determined using both moment analysis and the program NONMEM. The average terminal half-life was 10.6 h. The prolonged elimination was mainly due to a decrease in its metabolic clearance (0.25 l.min-1). The maintenance infusion dose of midazolam in such patients should be reduced. The time to recovery after stopping an infusion depends upon the amount of drug in the body at that time and a simulation of the plasma concentrations after various infusion regimens suggests that recovery will be delayed after prolonged (greater than 48 h) administration of midazolam to these patients. However, after shorter infusions (less than 12 h), redistribution of the drug away from the site of action was still occurring and recovery would be expected to be relatively rapid.

Pharmacokinetics and sedative effect of midazolam in connection with caesarean section performed under epidural analgesia.

Midazolam, the new investigational 1,4-benzodiazepine derivative with highly water-soluble salts, was studied as an anaesthesiological adjuvant in 11 patients undergoing elective caeserean section under epidural analgesia. I.v. administered midazolam, 0.075 mg/kg after delivery, caused a rapid and marked sedative effect, lasting for about 2-3 h. Short-lasting anterograde amnesia of about 30 to 60 min was reported as well. The serum levels of the parent drug and its active metabolites were determined in six cases by a radioreceptor assay and pharmacokinetic parameters were calculated on the basis of these levels by a two-compartment open model. Up to 3 h after midazolam administration, good correlation between the sedative effect and serum drug levels was found. The rapid but short-lasting action can be explained by the pharmacokinetic parameters of midazolam: a short distribution phase half-life (4.19 min), and a short elimination phase half-life (67.85 min) due to a high clearance value (13.18 ml/min/kg) and a moderate distribution volume (1.20 l/kg).