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Pharmacogenetics and chiral aspects of anti-asthma therapy

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Yee, Kwang Choon (2009) Pharmacogenetics and chiral aspects of anti-asthma therapy. PhD thesis, University of Tasmania.

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Abstract

Introduction: Asthma is a chronic inflammatory airway disease characterised by
recurrent symptoms. The available treatment options for the disease to date are
concentrated on symptom control. Treatment responses to most anti-asthma
medications show wide variation among populations and individuals. There is
evidence that genetic variations can affect the pharmacokinetic and pharmacodynamic
effects of medications, hence influencing treatment outcomes. The objective of this
research is to investigate the effect of some common genetic variations in enzymes
and proteins associated with the pharmacokinetic and pharmacodynamic properties of
anti-asthma medications.
Method: Observational studies were first carried out to examine plasma levels of
salbutamol enantiomers during disease exacerbation. Animal models were then
employed to study the distribution of salbutamol enantiomers into various tissues and
the role of the organic cation transport (OCT) system. The genetic determinants
(single nucleotide polymorphism (SNP) in the SULT1A3 enzyme) on the
pharmacokinetics of salbutamol enantiomers were investigated with a controlled
clinical study. A retrospective study was employed to investigate the genetic
determinants (microsatellite in ALOX5 and SNPs in ALOX5, LTC4S, LTA4H and
cysLTR1) of treatment outcome (pharmacodynamics) with montelukast therapy. A
comparison study was designed to explore the relationship between genetic variations
(SNPs in activator protein-1 (AP-1) related genes) and refractory asthma, with the
intention to gain more understanding of the role of genetic variations in the
pathophysiology of airway inflammation.
Result: The studies revealed wide variability among individuals in both the
pharmacokinetic and pharmacodynamic parameters of anti-asthma medications. The
studies observed some relatively high levels (>20 ng/ml) and uneven presentation of
salbutamol enantiomers (R:S ratio of 0.43) among patients who presented at the
emergency department with disease exacerbation. Animal models indicated an
enantioselective uptake and disposition of salbutamol (R:S ratio > 2.9) in cardiac and
skeletal muscle, but the model was unable to demonstrate the role of OCT systems.
The study did not find significant genetic influences in the pharmacokinetic
parameters of (R)- and (S)-salbutamol, mean difference (95%CI) in AUC (0-4h) were
-1.1 (-38 - 36) and -5.8 (-97 - 88) respectively. There was also no significant
relationship found between genetic determinants and the treatment response to
montelukast (p=0.12 for ALOX5 microsatellite, p>0.35 for all SNP determinants).
The study examined patients with refractory asthma and found no significant
differences in genetic determinants at AP-1 related genes (p>0.40) compared to
'regular' asthma.
Discussion: The results suggest that salbutamol enantiomer levels in the circulation
are widely variable between individuals. This work also suggests that there are no
overwhelming pharmacogenetic effects in the anti-asthma medications examined. The
sample size of the studies and the heterogeneous nature of genetic effects should be
taken into consideration in future asthma pharmacogenetic studies.

Item Type: Thesis (PhD)
Keywords: Asthma, Chiral drugs, Pharmacogenetics
Copyright Holders: The Author
Copyright Information:

Copyright 2009 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s).

Additional Information:

Available for use in the Library and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2009. Includes bibliographical references

Date Deposited: 04 Feb 2015 23:36
Last Modified: 11 Mar 2016 05:53
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