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Biolanalysis of ziprasidone and its S-methylated metabolite in serum using on-line extraction and liquid chromatography-masspectrometry
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Department of Analytical Chemistry, Stockholm University, Stockholm, Sweden.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The novel antipsychotic agent Ziprasidone, (Zip) was introduced for clinical prescription in Sweden in the early spring of 2001. As of yet, no bioanalytical procedure suitable for a Therapeutic Drug Monitoring (TDM)-service of the drug has been presented. Therefore a bioanalytical methodology utilising online extraction on RP-C4-ADS columns combined with ion-trap masspectrometric detection for determination of Zip and its S-methylated metabolite (Smd-Zip) was developed. The stability of the analytes in serum was determined for establishing a correct sample handling procedure.

The calibration model for Zip and Smd-Zip had a linear response function in the concentration range 20 to 500 and 15 to 300 nM, respectively. The intra- and inter-day coefficient of variance was below 10% for all calibrator levels for both Zip and Smd-Zip. Validation of the sample handling procedure showed that samples are stable in room temperature or refrigerator for 3 days. Repeated freeze/thaw cycles, for five times did not affect the Zip or Smd-Zip concentration. In essence these findings state the importance of a correct sampling procedure for a functional ID M-procedure.

The TDM-procedure was applied on 10 patient serum samples obtained from a naturalistic clinical setting. The obtained concentrations, ranging from 66 to 432 nM for Zip and 42 to 220 nM for Smd-Zip were within the dynamic range of the present methodology. Thus, a future utility for this newly developed method in a TDM-setting seems evident.

National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-84595OAI: diva2:560489
Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2012-10-15Bibliographically approved
In thesis
1. Bioanalytical development for application in therapeutic drug monitoring: focus on drugs used in psychiatry
Open this publication in new window or tab >>Bioanalytical development for application in therapeutic drug monitoring: focus on drugs used in psychiatry
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: Since the 1950s and onwards, many new psychoactive drugs have been successfully introduced in clinical practice. A common feature of these drugs is a profound metabolism before clearance from the body. Genetic and phenotypic factors among patients can be anticipated to interact with the metabolism and therefore a major variance in the drug concentration between patients upon the same dose may be found. In later years there has been an increasing awareness, that the individual drug metabolism and drug body disposition do not only refer to the parent compound and major metabolites but also to the separate enantiomers in the case of chiral drugs.

Bioanalytical methods for determination of drug concentrations have constantly been developed to assess the large pharmacokinetic variability of these drugs. Moreover, in the psychopharmacological practice these methods are often extended into a "Therapeutic Drug Monitoring (TDM) Service". A TDM service is used to determine the patient-specific drug analytical outcome in order to assess the precision in dose prescription as well as to recommend adequate dose adjustments for a particular patient.

Aim: The aim was to develop bioanalytical methods, utilising high performance liquid chromatography, for serum determinations in patients under chronic dosing schedules for some recently introduced drugs used in psychiatry.

Firstly, for the antidepressant drug reboxetine by an achiral methodology (paper I) consecutively extended to an enantioselective methodology for the individual enantiomers of the drug (paper II and III). Thereafter, after the evaluation of on-line extraction as an automated alternative to manually performed solid phase extraction for sample preparation (paper IV), apply on-line extraction in combination with ion-trap mass spectrometry detection for serum determination of the novel antipsychotic drug ziprasidone (paper V).

Results and Conclusion: The methodology described in paper I has been applied on more than 500 patient samples from the naturalistic clinical practice as well as from controlled clinical trials. The methodology has proven robust and reliable and, although manually performed, easy to handle. The kinetic outcome display a great variability in concentration outcome even within the same prescribed dose, i.e. through level samples in steady-state were found to be 660±400 nM on 8 mg/day.

Paper II, which describes the development of three approaches for direct chiral separation of reboxetine and O-deethylreboxetine enantiomers in the reversed phase mode, is in itself new and important. It is however, after applying MS2 detection, in paper III that the methodology is extended to include patients, i.e. patients from two separate clinical trials. Trial I comprised 23 patients on monotherapy with reboxetine and trial II comprised 47 patient from a naturalistic clinical setting. The pharrnacokinetic outcome displayed a S,S- over R,R-reboxetine ratio of about 0.5 with a rather pronounced inter-individual ratio (i.e. 0.2 to 0.9). The enantiomeric ratio did not correlate to the overall reboxetine concentration and the enantiomeric ratio was about 30% higher in females than in males. Repeated samples were analysed for trial I patients displaying an inter-individual coefficient of variation (CV) of about 17% meanwhile the intra-individual CV was about 4%. Calculating the noradrenaline reuptake inhibition (NARI) -activity out of the individual enantiomeric ratios showed that females may have a higher NARI-activity than males at a given reboxetine concentration.

Paper IV proves that online extraction offers a robust, reliable and, for the analyst, time saving alternative (above 80%) to manually performed off-line solid phase extraction for sample preparation (citalopram and its demethylated metabolites were used as model substances).

Paper V describes the development of a TDM process for ziprasidone and its S-methylated metabolite. The sample handling as well as the analytical process was subjected to a solid and satisfactory validation. It was proved that the lack of selectivity during on-line extraction can be compensated for by a selective form of detection, i.e. mass spectrometric detection.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 66 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 775
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-24800 (URN)7064 (Local ID)91-7373-534-5 (ISBN)7064 (Archive number)7064 (OAI)
Public defence
2003-02-28, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-15Bibliographically approved

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