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Pharmacology: Mechanism of Antihypertensive Action: In the absorption process in the body, candesartan cilexetil is rapidly hydrolyzed to the active metabolite candesartan, which exerts its antihypertensive action primarily by inhibiting the potent vasoconstrictor effect of angiotensin II through its antagonistic action at the angiotensin II type 1 (AT1) receptor in vascular smooth muscle, thereby reducing peripheral vascular resistance.
In addition, inhibitory effect on the release of aldosterone from adrenal gland mediated by AT1, receptor is considered to play a role in the antihypertensive action.
Amlodipine besilate acts as a dihydropyridine calcium channel antagonist, and is characterized by gradual onset of action and continuous effect.
Dihydropyridine calcium channel antagonist selectively binds to the membrane potential- dependent L-type calcium channels and reduces calcium influx into cells, causing relaxation of coronary or peripheral vascular smooth muscle.
Effect on the renin-angiotensin system: When candesartan cilexetil was administered repeatedly at a once daily dose of 1 - 12 mg, plasma renin activity and the plasma levels of angiotensin I and II were elevated.
Pharmacokinetics: Blood concentration: After a single oral administration of a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet, active metabolite candesartan and inactive metabolite M-II and unchanged amlodipine were detected in the blood, but the unchanged candesartan cilexetil was undetected.
Effect of meals: When a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet was administered to healthy adults after meal, the Cmax and the AUC of active metabolite candesartan were higher than those under fasting conditions. No changes were observed in the Cmax and AUC of amlodipine.
Urinary excretion: After a single oral administration of a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet, unchanged candesartan cilexetil was not detected in the urine, but the active metabolite candesartan, inactive metabolite M-II and unchanged amlodipine were excreted in the urine.
Metabolism: Candesartan cilexetil is metabolized to an active metabolite candesartan by carboxylesterase, and a part of it is further metabolized to inactive metabolite M-II by CYP2C9. However, compared with the blood concentration and urinary excretion of candesartan, those of M-II after administration of this drug to patients with essential hypertension are lower, indicating that the influence of genetic polymorphism of CYP2C9 on the blood concentration of candesartan is negligible.
Candesartan does not inhibit the metabolic activity of CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9- Arg, 2C19, 2D6, 2E1 and 3A4 (in vitro).
Amlodipine is mainly metabolized by CYP3A4, and unchanged component as well as nine metabolites are detected in the urine.
