liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Stereoselective determination of venlafaxine and its three demethylated metabolites in human plasma and whole blood by liquid chromatography with electrospray tandem mass spectrometric detection and solid phase extraction
Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology. (Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Linköping, Sweden)
Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. (Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Linköping, Sweden)
Show others and affiliations
2010 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, no 3, 583-590 p.Article in journal (Refereed) Published
Abstract [en]

A stereoselective method is described for simultaneous determination of the S- and R-enantiomers of venlafaxine and its three demethylated metabolites in human plasma and whole blood samples. This validated method involved LC/MS/MS with positive electrospray ionization and solid phase extraction. Chromatographic separation was performed on a 250 mm x 2.1mm Chirobiotic V column with a total run time of 35 min. In plasma, calibration curves were in the range of 1-1000 nM for the S- and R-enantiomers of venlafaxine and O-desmethylvenlafaxine, and 0.5-500 nM for N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. In whole blood the corresponding concentrations were 10-4000 and 5-2000 nM, respectively. The intra-day precision was <6.3% and the inter-day precision was <9.9% for plasma and <15% and <19% for whole blood. LLOQ ranged between 0.25 and 0.5 nM. No ion suppression/enhancement or other matrix effects were observed. The method was successfully applied for determination of venlafaxine and its metabolites in plasma from patients and whole blood samples from forensic autopsy cases.

Place, publisher, year, edition, pages
2010. Vol. 53, no 3, 583-590 p.
Keyword [en]
Venlafaxine; Enantiomers; LC–ESI-MS/MS; Metabolites; Human
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-58798DOI: 10.1016/j.jpba.2010.03.043PubMedID: 20435422OAI: oai:DiVA.org:liu-58798DiVA: diva2:345802
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12
In thesis
1. Genetic influence on enantiomeric drug disposition: Focus on venlafaxine and citalopram
Open this publication in new window or tab >>Genetic influence on enantiomeric drug disposition: Focus on venlafaxine and citalopram
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A molecule that is not identical to its mirror image is said to be chiral. A racemic mixture, or a racemate, is one that has equal amounts of S- and R-enantiomers of a chiral molecule. Two examples of frequently prescribed racemic drugs are the antidepressants venlafaxine (VEN) and citalopram (CIT). The R-enantiomer of VEN is a potent inhibitor of serotonin and noradrenaline reuptake, while the S-enantiomer is more selective in inhibiting serotonin reuptake. CIT is a selective serotonin reuptake inhibitor and the S-enantiomer is responsible for this effect. The R-enantiomer of CIT is therapeutically inactive, but displays other effects or side-effects. Due to the potential of different pharmacological and toxicological activities of the VEN and CIT enantiomers, it is of great interest to investigate the individual enantiomers of these drugs, concerning both pharmacokinetics and pharmacodynamics. For this purpose, it is necessary to develop stereoselective bioanalytical methods. A major clinical problem in the use of many drugs is the inter-individual variability in drug metabolism and response. Genetic variations contribute to this variability, including e.g. polymorphisms in the cytochrome P450 (CYP) enzymes. Approximately 7% of all Caucasians lack the polymorphic isoenzyme CYP2D6 and these individuals are classified as poor metabolisers. Both VEN and CIT are partly metabolised by CYP2D6. However, it is not completely known how CYP2D6 deficiency may influence the in vivo pharmacokinetics of these drugs, especially regarding the enantiomeric disposition. The overall aim of this thesis was to study the relationship between pharmacokinetics and pharmacogenetics for VEN and CIT, with emphasis on enantiomeric drug disposition in different biomatrices. In Paper I, a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for enantioselective determination of VEN and its three major metabolites was developed and applied in plasma from patients and whole blood samples from forensic autopsy cases. In Papers II and III, the genetic influence on enantiomeric drug disposition in serum and brain following administration of racemic CIT and VEN to Sprague-Dawley and Dark Agouti rats was studied. The female Sprague-Dawley and Dark Agouti rats are considered the animal counterparts of the human extensive and poor metaboliser CYP2D6 phenotypes, respectively. Significant quantitative strain-related differences in the pharmacokinetics of CIT and VEN, and their metabolites, were observed. The results indicate that the CYP2D enzymes display a significant impact on the stereoselective metabolism of these drugs. The findings also highlight the importance of comparing different rat strains when conducting experimental pharmacokinetic studies. In Paper IV, the relation between CYP2D6 genotype and the disposition of the enantiomers of VEN and its metabolites in femoral blood from forensic autopsy cases was studied. A substantial variation in the relationship between the S- and R-enantiomers of VEN, and metabolites, was found. In individuals lacking two functional CYP2D6 alleles, a low enantiomeric S/R VEN ratio was strongly related to a high S/R ratio for the main metabolite O-desmethylvenlafaxine. Hence, by using enantioselective analysis of VEN and O-desmethylvenlafaxine, it is possible to predict if a person is a poor metaboliser genotype/phenotype for CYP2D6.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 91 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1264
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72240 (URN)9789173930574 (ISBN)
Public defence
2011-12-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-11-23 Created: 2011-11-23 Last updated: 2017-12-12Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Kingbäck, MariaJosefsson, MartinKarlsson, LouiseAhlner, JohanBengtsson, FinnKugelberg, Fredrik CCarlsson, Björn

Search in DiVA

By author/editor
Kingbäck, MariaJosefsson, MartinKarlsson, LouiseAhlner, JohanBengtsson, FinnKugelberg, Fredrik CCarlsson, Björn
By organisation
Clinical Pharmacology Faculty of Health SciencesDepartment of Physics, Chemistry and BiologyThe Institute of TechnologyDepartment of Clinical Pharmacology
In the same journal
Journal of Pharmaceutical and Biomedical Analysis
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 153 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf