Relationship between the receptor occupancy profile and pleiotropic effects of angiotensin II receptor blockers. (10th January 2013)

• Record Type: Journal Article
• Authors: Ando, Hitoshi; Ushijima, Kentarou; Hosohata, Keiko; Saito, Tetsuo; Fujimura, Akio
• Is Part Of: British journal of clinical pharmacology. Volume 75:Number 2(2013:Feb.)
• Page Start: 415
• Page End: 422
• Publication Date: 2013-01-10
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/j.1365-2125.2012.04358.x
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp4358-sec-0001" sec-type="section"> <title>Aim</title> <p>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.</p> </sec> <sec id="bcp4358-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="bcp4358-sec-0003" sec-type="section"> <title>Results</title> <p>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 (<italic>r</italic> = −0.46 − −0.55, <italic>P</italic> < 0.05), but not the markers of insulin resistance (<italic>r</italic> = 0.02–0.15, <italic>P</italic> = 0.46–0.94).</p> </sec> <sec id="bcp4358-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>