Angiotensin II antagonism and plasma radioreceptor‐kinetics of candesartan in man

Abstract

AimsThe pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose-effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p. ]-angiotensin II). Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose-effect curves were fitted according to an E max model and dose ratios (DR) calculated from the antagonist induced rightward shifts. Results Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t 1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6-9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4-7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent K i -doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible. Conclusions A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off-rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…AT1 Receptor Blocker Pharmacology cilexetil administration in rats and dogs is 28 and 5%, respectively (Kondo et al, 1996). Radioreceptor assay techniques have yielded very similar estimates of pharmacokinetic parameters of candesartan as those obtained by classic analytical techniques (Malerczyk et al, 1998). Eprosartan is rapidly absorbed from the gastointestinal tract (t max 1-2 hours) with an absolute bioavailability of 13% (Tenero et al, 1998b).…”

“…2) is not surprising. A similar apparent K i dose for candesartan (1.9 mg) had been determined by the same investigators in an earlier study (Malerczyk et al, 1998). A direct comparative study from another investigator group found that irbesartan produced greater inhibition of vasoconstriction and greater occupancy in the radioreceptor assay than losartan or valsartan when recommended starting doses of all three ARBs were compared , indicating that standard doses of three ARBs fall on different parts of the relative doseresponse curve.…”

“…Antagonism of AT1R by various ARBs has also been tested in vivo in humans, mostly healthy volunteers, and, similar to the above animal studies, this was largely done for ANGinduced blood pressure elevations. Following the original study with losartan (Christen et al, 1991), such studies have been performed with candesartan (Delacretaz et al, 1995;Ogihara et al, 1995;Belz et al, 1997Belz et al, , 2000Malerczyk et al, 1998;Fuchs et al, 2000;Gleiter et al, 2004), irbesartan (Belz et al, 1999Maillard et al, 1999;Mazzolai et al, 1999), losartan (Munafo et al, 1992;Belz et al, 1997Belz et al, , 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999;Fuchs et al, 2000;Gleiter et al, 2004), telmisartan Stangier et al, 2001), and valsartan (Müller et al, 1994;Morgan et al, 1997;Belz et al, 1999Belz et al, , 2000Maillard et al, 1999;Mazzolai et al, 1999).…”

“…This approach even allows for the construction of Schild plots, which otherwise can only be done for in vitro assays, to determine drug affinity in vivo. Moreover, such radioreceptor assays can be seen as a more relevant way to study pharmacokinetics, and this has been validated against classic pharmacokinetic measurements not only for ARBs (Malerczyk et al, 1998) but also for antagonists at other types of receptors such as adrenoceptors (Wellstein et al, 1988;de Mey et al, 1993;Taguchi et al, 1998).…”

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy

“…75,76 It has recently been shown that, in fact, all AT 1 -receptor antagonists are competitive antagonists, with tight-binding and very slow dissociation from the receptor. 77 This is especially true for candesartan, 78 which has demonstrated higher direct angiotensin II antagonistic activity in vivo than irbesartan, valsartan and losartan. 79,80 Thus, the effects of candesartan are likely to be long lasting and less easily overcome by increased endogeneous angiotensin II.…”