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Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology. (medicin)
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Sweden.
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2011 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 2, 367-377 p.Article in journal (Refereed) Published
Abstract [en]

Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

Place, publisher, year, edition, pages
Springer , 2011. Vol. 215, no 2, 367-377 p.
Keyword [en]
abcb1ab . Blood–brain barrier . Knockout mice . P-glycoprotein . Pharmacodynamic . Pharmacokinetic .Venlafaxine
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68038DOI: 10.1007/s00213-010-2148-5ISI: 000289985700016PubMedID: 21191569OAI: oai:DiVA.org:liu-68038DiVA: diva2:415357
Note
The original publication is available at www.springerlink.com: Louise Karlsson, Christoph Hiemke, Björn Carlsson, Martin Josefsson, Johan Ahlner, Finn Bengtsson, Ulrich Schmitt and Fredrik C Kugelberg, Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model., 2011, Psychopharmacology, (215), 2, 367-377. http://dx.doi.org/10.1007/s00213-010-2148-5 Copyright: Springer Science Business Media http://www.springerlink.com/Available from: 2011-05-06 Created: 2011-05-06 Last updated: 2012-03-28
In thesis
1. P-glycoprotein and chiral antidepressant drugs: Pharmacokinetic, pharmacogenetic and toxicological aspects
Open this publication in new window or tab >>P-glycoprotein and chiral antidepressant drugs: Pharmacokinetic, pharmacogenetic and toxicological aspects
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The blood-brain barrier (BBB) is formed by the capillary endothelial cells, joined together by tight junctions, with transporter proteins. BBB acts to regulate the brain concentrations of substances including many drugs. Transport across the cells is necessary for a drug to ensure that the drug reaches the site of action and transport proteins such as P-glycoprotein (P-gp; ABCB1) can limit the entrance into various tissues, including the brain.

Molecules that are not superimposable on their mirror images and thus exist in two enantiomeric forms (enantiomers) are said to be chiral. A racemic compound is one composed of a 50:50 mixture of two enantiomers, S- and R-enantiomers. Two examples of frequently prescribed racemic drugs are the chiral antidepressants venlafaxine (VEN) and citalopram (CIT). The enantiomers of VEN possess different pharmacodynamic profiles where the R-enantiomer is a potent inhibitor of both serotonin and noradrenaline reuptake (SNRI), while the S-enantiomer is more selective in inhibiting serotonin reuptake (SSRI). The SSRI effect of CIT resides in the S-enantiomer, whereas the R-enantiomer is considered to be therapeutically inactive, or even that it counteracts the effects. The S-enantiomer of CIT is now available as a separate SSRI (escitalopram, EsCIT). VEN and CIT are also among the most commonly found drugs in forensic autopsy cases.

Few previous studies have examined a possible enantioselective activity of P-gp. Thus, the general aim of this thesis was to study the enantiomeric distribution of chiral antidepressant drugs, focusing on the role of P-gp in the BBB. For this purpose, a mouse model disrupted of the genes coding for P-gp (abcb1ab (-/-) mice) was used. Brain and serum concentrations of the enantiomers of VEN and CIT, and their major metabolites, were compared to the corresponding wild-type mice (abcb1ab (+/+) mice). The open-field locomotor and rearing activities were examined after chronic VEN administration. In addition to the animal studies, genetic and toxicological aspects of P-gp were studied in a forensic autopsy material, where intoxication cases were compared with cases that were not related to intoxications.

The brain to serum concentration ratios for VEN, CIT and EsCIT differed between knockout mice and wild-type mice, with 2-3 fold higher brain concentrations in mice with no expression of P-gp. Hence, all studied drugs, and their major metabolites, were substrates for P-gp. There was no evidence for a stereoselective P-gp mediated transport. The P-gp substrate properties were reflected in the open-field behavior test where the knockout mice displayed increased center activity compared with wild-type mice following chronic VEN exposure. The genotype distribution of ABCB1 SNPs C1236T, G2677T and C3435T in VEN positive cases was significantly (or borderline) different between the intoxication cases and the non-intoxication cases. This difference in genotype distribution was not observed for the CIT positive cases.

To conclude, the present work has led to an increased knowledge about how the enantiomers of VEN and CIT are affected by the BBB transporter P-gp. Using an animal model, VEN and CIT have proved to be actively transported out of the brain by P-gp and no difference was observed for the enantiomers with regard to P-gp transport. Further, the ABCB1 genotype distribution was different in intoxication cases compared with non-intoxication cases. Taken together, these findings offer the possibility that the expression of P-gp in humans may be a contributing factor for limited treatment response and increased risk of side-effects following antidepressant drug treatment.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1283
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76126 (URN)978-91-7393-003-1 (ISBN)
Public defence
2012-04-13, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
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Available from: 2012-03-28 Created: 2012-03-28 Last updated: 2012-03-28Bibliographically approved

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