Polymorphism of ORM1 is associated with the pharmacokinetics of telmisartan.
BACKGROUND
The pharmacokinetics (PKs) and pharmacodynamics (PDs) of telmisartan varies among the individuals, and the main causes remain unknown. The aim of this study was to evaluate the impact of ORM1, as well as ABCC2, ABCB1, ABCG2 and SLCO1B3 polymorphisms, on the disposition of the drug and BP change after taking 40 mg telmisartan in 48 healthy Chinese males.


METHODS
A total of 48 healthy males were included in this trial. Every volunteer ingested a single dose of 40 mg telmisartan, and the plasma drug concentration and blood pressure (BP) were measured up to 48 h.


RESULTS
In this study, the area under the plasma concentration-time curve (AUC) in the heterozygotes of ORM1 113AG was higher than that in the wild-type homozygotes, AUC(0-48) (113AA vs. 113AG, 1,549.18±859.84 ng·h/ml vs. 2,313.54±1,257.71 ng·h/ml, P = 0.033), AUC(0-∞) (113AA vs. 113AG, 1,753.13±1,060.60 ng·h/ml vs. 2,686.90±1,401.87 ng·h/ml, P = 0.016), and the change(%) of the diastolic blood pressure (DBP) from the baseline BP value also showed a significant difference between the ORM1 113AG and 113AA genotypes at 5 h after taking telmisartan (P = 0.026). This study also showed that the allele of ABCC2 C3972T would affected the disposition of telmsiartan and the DBP change significantly after taking the drug. However, the common SNPs of ABCG2 C421, ABCB1 C3435T, and SLCO1B3 T334G showed no impacts on the PKs of telmisartan or BP change(%) in our trial.


CONCLUSIONS
The ORM1 A113G polymorphism was associated with the PKs variability after taking telmsiartan, as well as ABCC2 C3972T. The heterozygotes of ORM1 113AG showed a larger AUC and a notable BP change(%) from the baseline compared with the wild-type.


BACKGROUND
Chinese Clinical Trial Registry ChiCTR-TNC-10000898.
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Hunan Key laboratory of Pharmacogenetics, Central South University, Changsha, Hunan, PRC.
Wang-Qing
WQ
Chen
Yan
Y
Shu
Qing
Q
Li
Lin-Yong
LY
Xu
Mary W
MW
Roederer
Lan
L
Fan
Lan-Xiang
LX
Wu
Fa-Zhong
FZ
He
Jian-Quan
JQ
Luo
Zhi-Rong
ZR
Tan
Yi-Jing
YJ
He
Hong-Hao
HH
Zhou
Xiang
X
Chen
Wei
W
Zhang
D000328:Adult; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D001565:Benzoates / Q000097:blood / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009961:Orosomucoid / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D000077333:Telmisartan; D055815:Young Adult
D001562:Benzimidazoles; D001565:Benzoates; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009961:Orosomucoid; D000077333:Telmisartan; C000715087:ABCC2 protein, human