Disposition of the new angiotensin II receptor antagonist candesartan cilexetil in rats and dogs.

The disposition of candesartan cilexetil (CAS 145040-37-5, TCV-116) was studied after oral administration of 14C-labeled drug to rats and dogs. Candesartan cilexetil was absorbed from the small intestine and hydrolyzed completely to the pharmacologically active metabolite M-I during absorption process. In the plasma of these animals, an appreciable amount of M-I was present with no detectable concentration of unchanged drug. The M-I concentration in rat plasma attained a peak (Cmax, 0.280 microgram/ml) 2.3 h (Tmax after dosing and then declined with an apparent half-life (t1/2) of 3.8 h. In dogs, Tmax, Cmax, and t1/2 of M-I were 1.3 h, 0.012 microgram/ml, and 4.3 h, respectively. The bioavailabilities of M-I in rats and dogs were 28 and 5%, respectively. M-I was distributed widely in the tissues including the blood vessels as target tissues, was metabolized partially to the glucuronide and M-II, and was eliminated predominantly into the feces via biliary excretion. The elimination of M-I from the blood vessels was slower than that from the plasma. The sustained antihypertensive effect of this drug seemed to be due to the slow elimination of M-I from the blood vessels. With daily oral dosing for 14 days, no appreciable amounts of drug-related compounds were accumulated in rat body.