edoc

Myelotoxicity of thienopyridines

Maseneni, Swarna. Myelotoxicity of thienopyridines. 2012, PhD Thesis, University of Basel, Faculty of Science.

[img]
Preview
PDF
12Mb

Official URL: http://edoc.unibas.ch/diss/DissB_10131

Downloads: Statistics Overview

Abstract

Ticlopidine, clopidogrel and prasugrel are thienopyridine derivatives used for inhibition of platelet aggregation in several cardiovascular diseases. Besides hepatotoxicity, also bone marrow toxicity may limit their use. The mechanisms associated with myelotoxicity of thienopyridines are currently unclear. Uncovering the mechanism by which thienopyridines lead to these adverse effects is therefore of great importance. In this thesis, three different cell systems which include human hematopoietic stem cells isolated from umbilical cord blood, neutrophils isolated from peripheral blood and human promyelocytic leukemia cell line were used. The main aims of this thesis were to investigate whether the mother substance and/or the active metabolites are responsible for myelotoxicity and whether the inactive clopidogrel metabolite clopidogrel carboxylate contributes to myelotoxicity. Apart from the well-known CYP-mediated metabolism of thienopyridines in liver, MPO present in neutrophils also metabolise clopidogrel, ticlopidine, prasugrel, and clopidogrel carboxylate. In contrast, clopidogrel carboxylate was not metabolized by human CYP3A4. MPO-dependant metabolism of clopidogrel, ticlopidine, prasugrel, and clopidogrel carboxylate showed dose dependent cytotoxicity. Similarly, CYP3A4-mediated metabolism showed dose dependent cytotoxicity of all drugs except clopidogrel carboxylate. Taking into account the pharmacokinetics in humans, we conclude that the myelotoxic principle of clopidogrel is most probably associated with metabolite formation from clopidogrel carboxylate by myeloperoxidase. For ticlopidine and prasugrel the mother substance itself and metabolites formed by myeloperoxidase are myelotoxic. Both mother substance and metabolites formed by MPO or CYP3A4 showed mitochondrial mediated cytotoxicity.
Advisors:Krähenbühl, Stephan
Committee Members:Odermatt, Alex
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)
Item Type:Thesis
Thesis no:10131
Bibsysno:Link to catalogue
Number of Pages:127 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:51
Deposited On:17 Jan 2013 09:09

Repository Staff Only: item control page