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

Abstract

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.

Determination of midazolam in human plasma by solid‐phase microextraction and gas chromatography/mass spectrometry

“…Therefore, our analytical approach, based on the extraction and instrumental detection of midazolam alone, cannot be applied when the detection and/or quantitation of the above metabolites are required, as in pharmacokinetic/pharmacodynamic studies 17,. 37 However, 4‐hydroxymidazolam is not detectable in human plasma following subtherapeutic midazolam doses,12 or detectable at sub‐ng/ml levels following therapeutic doses;25 in addition, the more important active metabolite 1‐hydroxymidazolam is always found in much lower plasma concentrations than midazolam 12,. 17 Thus, the described method may be usefully applied in cases of acute midazolam intoxication,38 within diagnostic procedures for brain death ascertainments,39–41 assays following fatal overdoses,6,, 24,, 42,, 43 or in cases of driving under the influence of drugs 44,.…”

Clinical Pharmacokinetic Monitoring of Midazolam in Critically Ill Patients

“…Among these is an increased volume of distribution, which results in a prolonged half-life. [13][14][15] Midazolam is an intermediate-to-high-extraction drug; therefore, clearance is largely dependent on hepatic blood flow. 4 Any factor affecting blood flow, including multiorgan failure, shock, or circulatory collapse, as well as the plethora of drugs administered to critical care patients, can affect the pharmacokinetics of midazolam.…”

Sub-clinical hepatic encephalopathy in cirrhotic patients is not aggravated by sedation with propofol compared to midazolam: A randomized controlled study

“…A major component of the half-life is the production of active metabolites that may have different half-lives. However, for midazolam, the initial metabolite, alpha-hydroxyl-midazolam, has a short half-life as well [16]. Thus, liver patients are at potentially greater risk for complications, including cardiopulmonary compromise, and possible precipitation or exacerbation of encephalopathy, including subclinical encephalopathy [8,17].…”