title: Simultaneous determination of levomepromazine, midazolam and their major metabolites in human plasma by reversed-phase liquid chromatography.
abstract: A sensitive and reliable high-performance liquid chromatographic (HPLC) assay is a prerequisite for pharmacokinetic analysis of continuous infusion of levomepromazine adjuvant to midazolam. We developed such a method to determine the levels of levomepromazine, midazolam and their major metabolites (levomepromazinesulfoxide, desmethyl-, didesmethyllevomepromazine, O-desmethyllevomepromazine and alpha-hydroxy-midazolam) simultaneously. Desmethylclomipramine was used as an internal standard (I.S.). The lower limit of quantification of this assay was set for levomepromazine 4.1 microg/l, levomepromazinesulfoxide 4.9 microg/l, O-desmethyllevomepromazine 18.4 microg/l, alpha-hydroxymidazolam 26.6 microg/l, midazolam 23.4 microg/l, didesmethyllevomepromazine 15.8 microg/l, and desmethyllevomepromazine 6.6 microg/l. The between- and within day assay variations were commonly below 5%. The recovery in human plasma for the different analytes varied between 85 and 11%. The accuracy of this assay varied between 95 and 105% for the different concentrations. The linearity of this assay was set between 25 and 800 microg/l (r(2)>0.999 of the regression line). The first results of pharmacokinetic analysis of midazolam indicated that half-life varied between 1.1 and 1.9 h. Pharmacokinetic analysis using a one-compartment model of levomepromazine revealed that the apparent volume of distribution was 4.1+/-2.4 l per kg lean body mass and the metabolic clearance was 309+/-225 l per hour per 70 kg. This assay proved to be robust and reproducible. It can reliably be used for further study of the pharmacokinetics of continuous infusion of levomepromazine.
authors.affiliation: Department of Clinical Pharmacy, Viecuri Medical Centre, Venlo, The Netherlands. p.t.horst@hccnet.nl
authors.forename: P G J
authors.initials: PG
authors.lastname: ter Horst
authors.forename: N A
authors.initials: NA
authors.lastname: Foudraine
authors.forename: G
authors.initials: G
authors.lastname: Cuypers
authors.forename: E A
authors.initials: EA
authors.lastname: van Dijk
authors.forename: N J J
authors.initials: NJ
authors.lastname: Oldenhof
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000097:blood* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood* / Q000493:pharmacokinetics; D008728:Methotrimeprazine / Q000097:blood* / Q000493:pharmacokinetics; D008874:Midazolam / Q000097:blood* / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D018712:Analgesics, Non-Narcotic; D006993:Hypnotics and Sedatives; D008728:Methotrimeprazine; D008874:Midazolam