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Determination of serum reboxetine enantiomers in patients on chronic medication with racemic reboxetine
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
2003 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, no 2, 174-182 p.Article in journal (Refereed) Published
Abstract [en]

The chiral compound reboxetine is used as a selective noradrenaline re-uptake inhibitor (NARI) for the treatment of major depressive disorders. The pharmacokinetic variability of the enantiomers of the drug (S,S- and R,R-reboxetine) was studied using stereoselective high-performance liquid chromatography with mass spectrometric detection in a controlled clinical monotherapy situation (trial I) and a naturalistic clinical setting (trial II). Trial I included patients receiving racemic reboxetine as 6-month monotherapy for treatment of major depressive disorder. Trough level serum samples in steady state were analyzed for the concentration of the reboxetine enantiomers in study weeks 4, 12, and 24. In a therapeutic drug monitoring setting (trial II), 47 patients on doses ranging from 4 to 16 mg daily, including much polypharmacy, trough level steady-state serum samples were analyzed by the same bioanalytical method. Data from trials I and II were assessed to determine the inter- and intraindividual pharmacokinetic outcomes. The results showed that the median S,S/R,R ratio in steady state was 0.5 and ranged from 0.22 to 0.88. It was also shown that women have an approximately 30% higher S,S/R,R ratio than men. The S,S/R,R ratios of reboxetine were not found to correlate with reboxetine concentrations. To investigate the NARI activity of a circulating serum reboxetine concentration, a recalculation of the determined enantiomeric concentrations to previously demonstrated experimental NARI potencies of the drug enantiomers was performed. This partly novel concept of estimating pharmacodynamic activity showed that the serum NARI activity in women tended to be higher than in men at a given reboxetine concentration. In conclusion, the variability in the NARI activity per nmol/L reboxetine and the variability in the concentration outcome of the reboxetine enantiomers may justify the use of enantioselective drug monitoring in the clinic. The gender aspects of the drug have to be further assessed.

Place, publisher, year, edition, pages
2003. Vol. 25, no 2, 174-182 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26798DOI: 10.1097/00007691-200304000-00006Local ID: 11406OAI: oai:DiVA.org:liu-26798DiVA: diva2:247348
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically 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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 775
National Category
Medical and Health Sciences
Identifiers
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)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-15Bibliographically approved

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Öhman, DanielCherma Yeste, Maria DoloresNorlander, BjörnBengtsson, Finn

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