title: Impact of pharmacokinetics and pharmacogenetics on the efficacy of pranlukast in Japanese asthmatics.
abstract: OBJECTIVE
  Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC(4) synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC(4) synthase gene polymorphisms, were also investigated.
  
  
  METHODS
  The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV(1) after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed.
  
  
  RESULTS
  Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC(4) synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05).
  
  
  CONCLUSIONS
  There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. ko-asano@qa2.so-net.ne.jp
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakade
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiomi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Oguma
authors.forename: Koichi
authors.initials: K
authors.lastname: Sayama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujita
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
mesh_terms: D000483:Alleles; D018927:Anti-Asthmatic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D001249:Asthma / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D002867:Chromones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D018927:Anti-Asthmatic Agents; D002867:Chromones; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; C047681:pranlukast