ABSTRACT
A liquid chromatographic-mass spectrometric assay with atmospheric pressure chemical ionization for quantification of ondansetron and its main metabolite 8-hydroxyondansetron in human plasma was presented. The enantiomeric separation was achieved on a Chiralcel OD-R column containing cellulose tris-(3,5-dimethylphenylcarbamate). The validation data were within the required limits. The assay was successfully applied to authentic plasma samples. Quantitative results from postoperative patients receiving ondansetron demonstrated a great interindividual variability in postoperative plasma drug concentrations, the metabolites were not detected in their unconjugated form. A wide variation in the S-(+)-/R-(-)-ondansetron concentration ratio between 0.14 and 7.18 is indicative for a stereoselective disposition or metabolism. In further studies CYP2D6 and CYP3A4 genotype dependent metabolism of ondansetron enantiomers as well as of co-administered drugs and clinical efficacy of the medication should be tested.
Subject(s)
Ondansetron/analogs & derivatives , Ondansetron/blood , Ondansetron/pharmacokinetics , Postoperative Nausea and Vomiting/blood , Serotonin 5-HT3 Receptor Antagonists/blood , Serotonin 5-HT3 Receptor Antagonists/pharmacokinetics , Antiemetics/blood , Antiemetics/chemistry , Antiemetics/pharmacokinetics , Antiemetics/therapeutic use , Chromatography, High Pressure Liquid , Drug Stability , Humans , Limit of Detection , Molecular Structure , Ondansetron/chemistry , Ondansetron/therapeutic use , Postoperative Nausea and Vomiting/drug therapy , Postoperative Nausea and Vomiting/metabolism , Serotonin 5-HT3 Receptor Antagonists/chemistry , Serotonin 5-HT3 Receptor Antagonists/therapeutic use , Stereoisomerism , Tandem Mass SpectrometryABSTRACT
Assignments of 1H and 13C NMR chemical shifts were made by means of heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC) experiments for ondansetron, and by means of 1H-1H correlation spectroscopy (1H-1H COSY) and two-dimensional nuclear Overhauser effect spectroscopy (NOESY) experiments for two novel metabolites (M1 and M2) of ondansetron. These two metabolites were isolated for the first time from Mucor circinelloides.
Subject(s)
Magnetic Resonance Spectroscopy , Ondansetron/analogs & derivatives , Ondansetron/chemistry , Carbon Isotopes/analysis , Hydrogen/analysis , Molecular Structure , Mucor/metabolism , Ondansetron/isolation & purification , Ondansetron/metabolism , StereoisomerismABSTRACT
The development of a radioimmunoassay, incorporating solid-phase sample extraction, suitable for the subnanogram per ml determination of ondansetron base in human plasma is described. The antiserum was raised in Soay sheep following primary and booster immunizations with an immunogen prepared by conjugating 9-(carboxypropyl)-ondansetron to bovine thyroglobulin. The radioligand consisted of ondansetron specifically tritium-labelled on the N-methyl group of the indole moiety. The solid-phase extraction method, using a cyanopropyl sorbent, was introduced to remove cross-reacting metabolites and to enhance assay sensitivity. The calibration range is 0.05-2.40 ng ml-1 using a 1 ml sample of human plasma; inter- and intra-assay bias and precision are < +/- 13% and < 10% over this concentration range, respectively. The assay drift, measured as the difference in concentration values for quality control samples assayed immediately before and after the sequence of test plasma samples, is < +/- 10% for run sizes of up to 54 samples.
