Pharmacodynamic and pharmacokinetic properties of an angiotensin II receptor antagonist--characterization by use of Schild regression technique in man.
OBJECTIVE
The pharmacodynamic properties of a new angiotensin II receptor antagonist (BAY 10-6734) in humans were to be quantitatively characterized from the rightward shifts of the agonist dose-response curves after administration of different doses of the antagonist.


METHODS
24 healthy male volunteers received single oral doses of 20-300 mg BAY 10-6734. Before and up to 23 h post dosing (p.d.) plasma was obtained for HPLC measurement of parent compound and active metabolite BAY 10-6735. Exogenous angiotensin II was infused in increasing dose steps until blood pressure had increased by +25 mmHg. Angiotensin II dose-response curves were fitted individually using the sigmoidal Emax model. From the antagonist-induced rightward shifts, as compared to a premedication curve, dose ratios (DR) were determined and DR-1 plotted versus applied dosages and measured plasma concentrations. From these Schild regression plots the fictive doses and concentration (Ki) inducing a DR-1 = 1, i.e. a 2-fold shift in agonist dose-response curves, were derived. The "doubling (t2.0) time" of the apparent Ki doses was calculated.


RESULTS
BAY 10-6734 dose-dependently induced rightward shifts of the angiotensin II blood pressure response curves, mean maximum DR at 2 h p.d. ranged from 42 (80 mg) to 216 (300 mg), and at 23 h p.d. decreased to about 2 (80 mg) to 4 (300 mg). Pharmacodynamic (3.4-4.6 h) and pharmacokinetic half-lives (3.4-4.3 h) were nearly identical. Apparent Ki doses increased from about 1-2 mg at 2 h p.d. to about 80-100 mg at 23 h p.d., their time course revealed a doubling (t2.0) time of 3.5-3.8 h. A Ki concentration of about 10 micrograms/l was obtained for the active metabolite BAY 10-6735.


CONCLUSIONS
Oral administration of BAY 10-6734 in man antagonized angiotensin II dose blood pressure response curves in a dose-dependent manner. The time kinetics of the pharmacodynamic effect, derived from the decay of DR-1 values, as well as the doubling time of the apparent Ki values well agreed with the pharmacokinetic half-life. Schild regression revealed competitive angiotensin II antagonistic properties within the dose/concentration range tested. This technique was shown to be an adequate means to evaluate pharmacodynamic potency and kinetic behavior of an angiotensin II receptor antagonist in vivo.
Breithaupt-Grögler
K
K
Center of Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz/Wiesbaden, Germany.
Malerczyk
C
C
Belz
G G
GG
Butzer
R
R
Herrmann
V
V
Stass
H
H
Wensing
G
G
D000284:Administration, Oral; D000328:Adult; D000804:Angiotensin II / Q000008:administration & dosage; D057911:Angiotensin Receptor Antagonists; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D012044:Regression Analysis; D013777:Tetrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
D057911:Angiotensin Receptor Antagonists; C110043:BAY 10-6735; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C109119:embusartan