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Pharmacokinetics and pharmacodynamics of pentoxifylline and metabolites

Magnusson, Marie V LU (2009) In Lund University Faculty of Medicine Doctoral Dissertation Series 2009:29.
Abstract
Pentoxifylline is a haemorheologic drug with complex pharmacokinetics and pharmacodynamics due to both reversible metabolism and the formation of active metabolites. In humans, pentoxifylline is metabolised to at least seven phase 1 metabolites (M1-M7). The reversible metabolism of pentoxifylline to the enantiomers of M1 has only been partly studied.



This thesis investigates the pharmacokinetics of pentoxifylline and metabolites and their contributions to the haemorheological effects.



When pentoxifylline is administered either orally or intravenously to healthy humans the plasma concentrations of M5 and S-M1 are higher than the pentoxifylline concentrations, whereas the ones for M4 are lower and R-M1... (More)
Pentoxifylline is a haemorheologic drug with complex pharmacokinetics and pharmacodynamics due to both reversible metabolism and the formation of active metabolites. In humans, pentoxifylline is metabolised to at least seven phase 1 metabolites (M1-M7). The reversible metabolism of pentoxifylline to the enantiomers of M1 has only been partly studied.



This thesis investigates the pharmacokinetics of pentoxifylline and metabolites and their contributions to the haemorheological effects.



When pentoxifylline is administered either orally or intravenously to healthy humans the plasma concentrations of M5 and S-M1 are higher than the pentoxifylline concentrations, whereas the ones for M4 are lower and R-M1 much lower. In-vitro studies showed that this can be mainly explained by a 15 times faster formation of S-M1 than R-M1 from pentoxifylline. Had the enantiomers been present at equal concentrations the reversible metabolism would have been 4 times faster from S-M1 than from R-M1.



Pentoxifylline, R-M1, and M5 increases retinal blood flow after administration of pentoxifylline to healthy humans.



In the following potency order R-M1, rac-M1, S-M1, pentoxifylline and M4 significantly inhibit platelet aggregation in a concentration-dependent manner in whole blood from healthy humans.



The thesis also includes a phase two, double-blind, placebo-controlled randomised clinical trial investigating pentoxifylline and vitamin E treatment for prevention of radiation-induced side effects in 83 women with breast cancer. The study showed that the combination of pentoxifylline and vitamin E was well tolerated and may be used for prevention of some radiation-induced side effects, e.g. increased arm volume and pain described as stiffness in the skin. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Uppugunduri, Srinivas, Institutionen för klinisk och experimentell medicin, IKE, Linköpings Universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
pharmacokinetics, Pentoxifylline, metabolites, pharmacodynamics
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2009:29
pages
100 pages
publisher
Lund University, Faculty of Medicine
defense location
Föreläsningssalen, byggnad 11, Barngatan 2A, 2 vån, Universitetssjukhuset i Lund
defense date
2009-04-18 10:15
ISSN
1652-8220
ISBN
978-91-86253-16-5
language
English
LU publication?
yes
id
c3e04e5a-ed66-4333-aef3-48f4d71ae3aa (old id 1365881)
date added to LUP
2009-04-01 08:35:32
date last changed
2016-09-19 08:44:49
@phdthesis{c3e04e5a-ed66-4333-aef3-48f4d71ae3aa,
  abstract     = {Pentoxifylline is a haemorheologic drug with complex pharmacokinetics and pharmacodynamics due to both reversible metabolism and the formation of active metabolites. In humans, pentoxifylline is metabolised to at least seven phase 1 metabolites (M1-M7). The reversible metabolism of pentoxifylline to the enantiomers of M1 has only been partly studied. <br/><br>
<br/><br>
This thesis investigates the pharmacokinetics of pentoxifylline and metabolites and their contributions to the haemorheological effects. <br/><br>
<br/><br>
When pentoxifylline is administered either orally or intravenously to healthy humans the plasma concentrations of M5 and S-M1 are higher than the pentoxifylline concentrations, whereas the ones for M4 are lower and R-M1 much lower. In-vitro studies showed that this can be mainly explained by a 15 times faster formation of S-M1 than R-M1 from pentoxifylline. Had the enantiomers been present at equal concentrations the reversible metabolism would have been 4 times faster from S-M1 than from R-M1.<br/><br>
<br/><br>
Pentoxifylline, R-M1, and M5 increases retinal blood flow after administration of pentoxifylline to healthy humans. <br/><br>
<br/><br>
In the following potency order R-M1, rac-M1, S-M1, pentoxifylline and M4 significantly inhibit platelet aggregation in a concentration-dependent manner in whole blood from healthy humans.<br/><br>
<br/><br>
The thesis also includes a phase two, double-blind, placebo-controlled randomised clinical trial investigating pentoxifylline and vitamin E treatment for prevention of radiation-induced side effects in 83 women with breast cancer. The study showed that the combination of pentoxifylline and vitamin E was well tolerated and may be used for prevention of some radiation-induced side effects, e.g. increased arm volume and pain described as stiffness in the skin.},
  author       = {Magnusson, Marie V},
  isbn         = {978-91-86253-16-5},
  issn         = {1652-8220},
  keyword      = {pharmacokinetics,Pentoxifylline,metabolites,pharmacodynamics},
  language     = {eng},
  pages        = {100},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Pharmacokinetics and pharmacodynamics of pentoxifylline and metabolites},
  volume       = {2009:29},
  year         = {2009},
}