title: UGT1A1*28 is associated with greater decrease in serum K⁺ levels following oral intake of procaterol.
abstract: OBJECTIVE
  Procaterol is a potent β2-agonist frequently used for the management of asthma and chronic obstructive pulmonary disease. The efficacy and adverse effects of β2-agonists are heterogeneous in individual patients, which may be partly caused by genetic variations in metabolizing enzymes and receptor molecules. The present study was designed to analyze the relationship between gene polymorphisms and physiological effects of procaterol in healthy subjects.
  
  
  METHODS
  Ninety-two non-smoking healthy volunteers were given 1 µg/kg body weight (max 50 µg) of procaterol as a dry syrup preparation, and the serum concentrations of procaterol, serum K(+), and the physical responses were monitored for 240 min. We genotyped β2-adrenergic receptor (ADRB2) (Arg16Gly and Gln27Glu), cytochrome P450 3A4 (rs2246709, rs4646437), and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) (rs4148323 [allele A, *6], rs12479045, rs4148328, rs4663971, rs12052787, rs4148329, A (TA)6/7 TAA [seven-repeat allele, *28]). Procaterol concentrations in serum were measured by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  No gene polymorphisms affected serum procaterol concentrations. Meanwhile, overall serum K(+) level changes were significantly lower in carriers of UGT1A1*28 than in non-carriers after correcting for strong effects of serum procaterol concentrations and baseline K(+) levels. No other polymorphisms were associated with serum K(+) levels. None of polymorphisms of ADRB2 were associated with any physical responses.
  
  
  CONCLUSIONS
  The present study indicates that significant hypokalemia may occur in carriers of UGT1A1*28 by systemic administration of procaterol and potentially by other β2-agonists metabolized in the liver.
authors.affiliation: Division of Respiratory Medicine and Allergology, Department of Internal Medicine, Aichi Medical University , Nagakute , Japan .
authors.forename: Norihito
authors.initials: N
authors.lastname: Yokoe
authors.forename: Etsuro
authors.initials: E
authors.lastname: Yamaguchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Ayumu
authors.initials: A
authors.lastname: Takahashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Baba
authors.forename: Masahiko
authors.initials: M
authors.lastname: Gosho
authors.forename: Shoshiro
authors.initials: S
authors.lastname: Okada
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000328:Adult; D001249:Asthma / Q000235:genetics*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D011110:Polymorphism, Genetic; D011188:Potassium / Q000097:blood*; D017265:Procaterol / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D011188:Potassium; D017265:Procaterol; D018343:Receptors, Adrenergic, beta-2; D000099148:UGT1A1 Enzyme; C553443:ADRB2 protein, human; C510163:CYP3A4 protein, human
keywords: cytochrome P450; single nucleotide polymorphism; uridine diphosphate glucuronosyltransferase 1A1; β2-adrenergic receptor