Relationship between the receptor occupancy profile and pleiotropic effects of angiotensin II receptor blockers.
OBJECTIVE
To investigate whether (i) angiotensin receptor occupying profiles of angiotensin II receptor blockers (ARBs) vary among the drugs and (ii) such differences contribute to the degree of their pleiotropic effects.


METHODS
In a randomized, three phase crossover study, nine hypertensive patients received repeated doses (each recommended starting dose for 7 days and then each maximum recommended dose for 20 days) of irbesartan, valsartan and candesartan. The time course profiles and trough level of receptor occupancy were determined on days 7 and 28, respectively. The pleiotropic effect related parameters were measured on days 0 and 28 in each trial.


RESULTS
Of the pleiotropic effect related parameters investigated, urinary 8-isoprostane, fasting serum insulin and homeostasis model assessment of insulin resistance index were more suppressed after 4 weeks treatment with irbesartan than after candesartan and valsartan therapy, respectively. The maximum, area under the curve and trough values of receptor occupancy significantly differed between the ARBs [geometric mean (and 95% CI) of trough value 18.1 (12.9, 25.3) for irbesartan, 9.6 (6.0, 15.3) for valsartan and 5.5 (2.8, 10.8) for candesartan, respectively] and were negatively correlated with the change in urinary 8-isoprostane (r = -0.46 - -0.55, P < 0.05), but not the markers of insulin resistance (r = 0.02-0.15, P = 0.46-0.94).


CONCLUSIONS
Our results demonstrate that the receptor occupying profiles are different among the ARBs. This class of drugs might have both receptor occupancy dependent and independent pleiotropic effects.
Division of Clinical Pharmacology, Department of Pharmacology, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Hitoshi
H
Ando
Kentarou
K
Ushijima
Keiko
K
Hosohata
Tetsuo
T
Saito
Akio
A
Fujimura
D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D000077405:Irbesartan; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D011869:Radioligand Assay; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D055815:Young Adult
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007328:Insulin; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C075750:8-epi-prostaglandin F2alpha; D000068756:Valsartan; D015237:Dinoprost; D014633:Valine; D000077405:Irbesartan; C081643:candesartan