Pharmacogenetics and chiral aspects of anti-asthma therapy

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.