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Genetic influence on enantiomeric drug disposition: Focus on venlafaxine and citalopram
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-72240ISBN: 9789173930574 (print)OAI: oai:DiVA.org:liu-72240DiVA: diva2:458660
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
List of papers
1. 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
Open this publication in new window or tab >>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
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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.

Keyword
Venlafaxine; Enantiomers; LC–ESI-MS/MS; Metabolites; Human
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58798 (URN)10.1016/j.jpba.2010.03.043 (DOI)20435422 (PubMedID)
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12
2. Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats
Open this publication in new window or tab >>Cytochrome P450-Dependent Disposition of the Enantiomers of Citalopram and Its Metabolites: In Vivo Studies in Sprague-Dawley and Dark Agouti Rats
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2011 (English)In: Chirality, ISSN 0899-0042, E-ISSN 1520-636X, Vol. 23, no 2, 172-177 p.Article in journal (Refereed) Published
Abstract [en]

The female Sprague-Dawley (SD) and Dark Agouti (DA) rats are considered the animal counterparts of the human extensive and poor metabolizer cytochrome P450 (CYP) 2D6 phenotypes, respectively. The aim of this work was to study possible rat strain differences in the steady-state pharmacokinetics of the (+)-(S)- and (-)-(R)-enantiomers of citalopram and its demethylated metabolites. A chronic drug treatment regimen (15 mg/kg daily) was implemented for 13 days in separate groups of SD (n 5 9) and DA (n 5 9) rats by using osmotic pumps. The concentrations of citalopram and two major metabolites in serum and two brain regions were analyzed by an enantioselective high-performance liquid chromatography assay. Higher serum and brain levels of citalopram and demethylcitalopram, but lower levels of didemethylcitalopram, were observed in DA rats when compared with SD rats. The enantiomeric (S/R) concentrations ratios of citalopram were lower in the DA rats when compared with the SD rats (0.53 +/- 0.05 vs. 0.80 +/- 0.03, P andlt; 0.001), indicating a possibly decreased capacity in the metabolism of the (-)-(R)-enantiomer in the DA rats. This study shows that CYP2D deficiency results in steady-state pharmacokinetic differences of the enantiomers of citalopram and its metabolites.

Place, publisher, year, edition, pages
John Wiley and Sons, Ltd, 2011
Keyword
citalopram, CYP2D6, Dark Agouti, enantiomer, pharmacokinetics, Sprague-Dawley
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65566 (URN)10.1002/chir.20901 (DOI)000285976800013 ()
Available from: 2011-02-11 Created: 2011-02-11 Last updated: 2017-12-11
3. Pharmacokinetic Differences in the Disposition of the Enantiomers of Venlafaxine and Its Metabolites in Sprague-Dawley and Dark Agouti Rats
Open this publication in new window or tab >>Pharmacokinetic Differences in the Disposition of the Enantiomers of Venlafaxine and Its Metabolites in Sprague-Dawley and Dark Agouti Rats
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Venlafaxine is a frequently prescribed racemic antidepressant drug worldwide, consisting of two enantiomers that exhibit similar but not identical biological activity profiles. Venlafaxine is extensively metabolised by the cytochrome P450 (CYP) system. CYP2D6 is involved in the formation of O-desmethylvenlafaxine (Odm-venlafaxine) and CYP3A4 in the formation of Ndesmethylvenlafaxine (Ndm-venlafaxine). The female Dark Agouti and Sprague-Dawley rats are considered the animal counterparts of the human CYP2D6 poor and extensive metaboliser phenotypes, respectively. Since CYP2D6 seems to play a major role in the metabolism of venlafaxine, the aim of this work was to study possible differences in the pharmacokinetics of the enantiomers of venlafaxine and its metabolites in these two different rat strains. Following single administration of racemic venlafaxine (15 mg/kg) serum and brain samples were collected and the concentrations of the enantiomers of venlafaxine and its three major metabolites were determined using an enantioselective LC/MS/MS method. Higher serum and brain concentrations of venlafaxine were observed in Dark Agouti rats as compared to Sprague-Dawley rats (p=0.0002). In relation to the Odm-venlafaxine concentration, the Ndmvenlafaxine concentrations were much higher in Dark Agouti rats than in Sprague-Dawley rats (p<0.0001). The enantiomeric (S/R) venlafaxine ratios were almost two times higher in Dark Agouti rats than in Sprague-Dawley rats, which was observed in both serum and brain (p<0.0001). The present results give hints for possible differences in the pharmacokinetics of venlafaxine in human extensive and poor metaboliser CYP2D6 phenotype subjects.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72239 (URN)
Available from: 2011-11-23 Created: 2011-11-23 Last updated: 2011-11-23Bibliographically approved
4. Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood
Open this publication in new window or tab >>Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood
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2012 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, no 1-3, 124-134 p.Article in journal (Refereed) Published
Abstract [en]

Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
CYP2D6; Enantiomers; Forensic toxicology; Postmortem toxicology; Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72238 (URN)10.1016/j.forsciint.2011.07.034 (DOI)000298634900032 ()21840145 (PubMedID)
Note

Funding agencies|Forensic Science Center of Linkoping University||National Board of Forensic Medicine in Sweden||Swedish Research Council| 2009-4740 |

Available from: 2011-11-23 Created: 2011-11-23 Last updated: 2017-12-08Bibliographically approved

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