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Relationship between the receptor occupancy profile and pleiotropic effects of angiotensin II receptor blockers
Author(s) -
Ando Hitoshi,
Ushijima Kentarou,
Hosohata Keiko,
Saito Tetsuo,
Fujimura Akio
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04358.x
Subject(s) - irbesartan , candesartan , valsartan , medicine , receptor , endocrinology , angiotensin ii , insulin resistance , angiotensin ii receptor type 1 , pharmacology , insulin , blood pressure
Aim 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.