β2-肾上腺素能受体基因多态性对沙丁胺醇支气管扩张药效学的影响。

Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics.

作者信息

Lima J J, Thomason D B, Mohamed M H, Eberle L V, Self T H, Johnson J A

机构信息

Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis, USA.

出版信息

Clin Pharmacol Ther. 1999 May;65(5):519-25. doi: 10.1016/S0009-9236(99)70071-8.

DOI:10.1016/S0009-9236(99)70071-8

PMID:10340917

Abstract

OBJECTIVE

To determine whether genetic polymorphisms of the beta2-adrenergic receptor gene affect the relationship between albuterol (INN, salbutamol) plasma concentrations and the forced expiratory volume in 1 second (FEV1) in subjects with moderate asthma.

METHODS

Sixteen clinically stable patients with moderate asthma who participated in a pharmacokinetic-pharmacodynamic study of albuterol volunteered to provide a blood sample for determination of beta2-adrenergic receptor genotype. FEV1 and plasma concentrations of albuterol were determined at various times after administration of an oral solution that contained 8 mg albuterol. Patients withheld inhaled beta2-agonist and corticosteroid therapy 12 and 24 hours, respectively, before the study. beta2-Adrenergic receptor genotype was determined by polymerase chain reaction with allele-specific oligonucleotide hybridization.

RESULTS

Albuterol-evoked FEV1 was higher and the response was more rapid in Arg16 homozygotes compared with the cohort of carriers of the Gly16 variant: Maximal percentage increase in FEV1 (%deltaFEV1), 18% versus 4.9% (P < .03); area under FEV1 albuterol concentration curve, 194%.mL/ng versus 30%.mL/ng (P < .05); initial slope (dE/dC), 1.43%.mL/ng versus 0.55%.mL/ng (P < .003).

CONCLUSIONS

The beta2-adrenergic receptor gene polymorphism is a major determinant of bronchodilator response to albuterol. Future pharmacodynamic studies of beta2-agonists should include determination of 02-adrenergic receptor genotype.

摘要

目的

确定β2 - 肾上腺素能受体基因的遗传多态性是否会影响中度哮喘患者中沙丁胺醇（国际非专利药品名称，舒喘灵）血浆浓度与一秒用力呼气量（FEV1）之间的关系。

方法

16名参与沙丁胺醇药代动力学 - 药效学研究的临床稳定的中度哮喘患者自愿提供血样以测定β2 - 肾上腺素能受体基因型。在给予含8 mg沙丁胺醇的口服溶液后的不同时间测定FEV1和沙丁胺醇的血浆浓度。患者在研究前分别停用吸入性β2 - 激动剂和皮质类固醇治疗12小时和24小时。通过聚合酶链反应与等位基因特异性寡核苷酸杂交来确定β2 - 肾上腺素能受体基因型。

结果

与携带Gly16变体的队列相比，Arg16纯合子中沙丁胺醇诱发的FEV1更高且反应更快：FEV1的最大百分比增加（%δFEV1），分别为18%和4.9%（P < 0.03）；FEV1 - 沙丁胺醇浓度曲线下面积，分别为194%·mL/ng和30%·mL/ng（P < 0.05）；初始斜率（dE/dC），分别为1.43%·mL/ng和0.55%·mL/ng（P < 0.003）。