Angiotensin II antagonism and plasma radioreceptor-kinetics of candesartan in man.
OBJECTIVE
The 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.l.c.


METHODS
Twelve healthy male volunteers received single oral doses of 4, 8 and 16 mg candesartan cilexetil and placebo. Plasma was obtained for h.p.l.c. and r.r.a. (receptors: rat lung; radioligand: [125I-Sar1Ile8]-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 Emax 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 t1/2 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 Ki-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.
Malerczyk
C
C
Center for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz/Wiesbaden, Germany.
Fuchs
B
B
Belz
G G
GG
Roll
S
S
Butzer
R
R
Breithaupt-Grögler
K
K
Herrmann
V
V
Magin
S G
SG
Högemann
A
A
Voith
B
B
Mutschler
E
E
D000284:Administration, Oral; D000328:Adult; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C077793:candesartan cilexetil; C081643:candesartan