The relationship between the plasma concentration of irbesartan and the antihypertensive response is disclosed by an angiotensin II type 1 receptor polymorphism: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) Trial.
BACKGROUND
The aim of this study was to investigate the effect of the plasma concentration of irbesartan, a specific angiotensin II type 1 receptor (AT1R) antagonist, and the blood pressure response in relation to AT1R gene polymorphisms.


METHODS
Plasma irbesartan was analyzed in 42 patients with mild-to-moderate hypertension and left ventricular hypertrophy from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) trial, who were treated with irbesartan as monotherapy for 12 weeks. Blood pressure and irbesartan concentration were measured at trough, i.e., 24 +/- 3 h after the last dose. Five AT1R gene polymorphisms were analyzed by minisequencing.


RESULTS
Neither the plasma concentration of irbesartan, nor any of the AT1R polymorphisms were associated with the blood pressure response to irbesartan treatment. However, the interaction term between the plasma concentration of irbesartan and the AT1R C5245T polymorphism was related to the reduction in systolic blood pressure after 12 weeks of treatment (P = 0.025). Furthermore, the plasma concentration of irbesartan was related to the change in systolic blood pressure in individuals homozygous for the AT1R 5245 T allele (r = -0.56, P = 0.030), but not for other genotypes.


CONCLUSIONS
There was an association between plasma concentrations of irbesartan and the blood pressure response for hypertensive patients with AT1R 5245 TT. Because of the small sample size, this study needs to be viewed as hypothesis generating. This is the first study, to our knowledge, indicating that the concentration-response relationship of an antihypertensive drug may be genotype dependent.
Kurland
Lisa
L
Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. lisa.kurland@medsci.uu.se
Hallberg
Pär
P
Melhus
Håkan
H
Liljedahl
Ulrika
U
Hashemi
Nashmil
N
Syvänen
Ann-Christine
AC
Lind
Lars
L
Kahan
Thomas
T
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000097:blood / Q000627:therapeutic use*; D001262:Atenolol / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000097:blood / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D000077405:Irbesartan; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D013548:Sweden; D013777:Tetrazoles / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D001262:Atenolol; D000077405:Irbesartan