ANGIOTENSIN-II ANTAGONISM AND PLASMA RADIORECEPTOR-KINETICS OF CANDESARTAN IN MAN

Aims The pharmacodynamic properties of the angiotensin II antagonist c andesartan in humans were assessed from the rightward shifts of angiot ensin TI dose-effect curves (Schild regression technique). The pharmac okinetic characteristics were determined by radioreceptor assay (r.r.a .) and h.p.l.c. Methods Twelve healthy male volunteers received single oral doses of 4, 8 and 16 mg candesartan cilexetil and placebo. Plasm a was obtained for h.p.l.c. and r.r.a. (receptors: rat lung; radioliga nd: [I-125-Sa(1) Ile(8)]-angiotensin II). Before and up to 24 h post d osing angiotensin II was infused in ascending dose steps until blood p ressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose-effect curves were fitted according to an E-max mo del and dose ratios (DR) calculated from the antagonist induced rightw ard 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 t o 4-7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent K-i-doses (derived fi-om 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 counterclockwi se hysteresis was visible. Conclusions A longer persistence of the ant agonistic effect at the receptor site than expected by the presence in plasma indicates a slow off-rate of candesartan cilexetil from in viv o receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.