Abstract
Background: The benzodiazepine midazolam is widely used pre- and intraoperatively in intensive care units. 1´-OH-midazolam, one of the major metabolites, is pharmacologically active. Accumulation of 1´-OH-midazolam, e.g. due to hepatic dysfunction or renal insufficiency, may therefore enhance pharmacological activity. Growing evidence suggests that sex, age, drug interactions, and inflammation also have an impact on midazolam disposition and activity. Due to the complex interplay of these factors, finding the optimal midazolam dose for each critically ill patient is challenging. Methods: We aimed to elucidate the factors that contribute significantly to pharmacokinetics of midazolam and its main metabolites in patients undergoing cardiac surgery. We collected serum and urine samples from 15 patients 1, 2, 3, 4, and 5 hours after the beginning of cardiac surgery and determined the concentrations of midazolam, 1´-OH-midazolam, 4-OH-midazolam, 1´-OH-midazolam-β-D-glucuronide, and 4-OH-midazolam- β-D-glucuronide by LC-MS/MS. Results: Oxidation to 4-OH-midazolam and subsequent glucuronidation played a role in metabolism and elimination of midazolam in our patient cohort. Patients showed relatively variable concentrations of midazolam and its metabolites, due to differences in midazolam dose and administration routes, demographic and clinical parameters. Thus, we evaluated pharmacokinetic parameters for individual patients and not for the whole patient cohort. We established a logarithmic multiple regression model linking urinary concentrations of midazolam, 1´-OH-midazolam, and 1´-OH-midazolam-β-D-glucuronide with explanatory variables. Conclusion: Our model linked urinary concentrations of midazolam, 4-OH-midazolam, and 1’-OH-midazolam- β-D-glucuronide to serum concentration, age, surgery infusion volume, creatinine concentration, and/or body temperature.
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