UGT1A1*28 is associated with greater decrease in serum K⁺ levels following oral intake of procaterol

Abstract

Background and 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. Conclusion: 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.

• β₂-adrenergic receptor
• cytochrome P450
• uridine diphosphate glucuronosyltransferase 1A1
• single nucleotide polymorphism

Acknowledgements

We thank Ms. Junko Kamiya for her excellent technical assistance.

Declaration of interest

The authors report no conflicts of interest.

This work was supported in part by a grant from the Strategic Research Foundation Grant-aided Project for Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (MEXT), 2011-2015 (S1101027), and by a grant from the Ministry of Health Labor and Welfare (The Project for Establishment and Utilization of a Guideline for Tailor-made Treatment and Management of Allergy, 2004–2009), Japan.

Supplementary material available online

Supplementary Tables 1–4