DISPOSITION OF THE NEW ANGIOTENSIN-II RECEPTOR ANTAGONIST CANDESARTANCILEXETIL IN RATS AND DOGS

The disposition of candesartan cilexetil (GAS 145040-37-5, TCV-116) wa s studied after oral administration of C-14-labeled drug to rats and d ogs. Candesartan cilexetil was absorbed from the small intestine and h ydrolyzed completely to the pharmacologically active metabolite M-I du ring absorption process. In the plasma of these animals, an appreciabl e amount of M-I was present with no detectable concentration of unchan ged drug. The M-I concentration in rat plasma attained a peak (C-max, 0.280 mu g/ml) 2.3 h (T-max) after dosing and then declined with an ap parent half-life (t(1/2)) Of 3.8 h. In dogs, T-max, C-max, and t(1/2) Of M-I were 1.3 h, 0.012 mu g/ml, and 4.3 h, respectively. The bioavai labilities 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 t arget 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 fr om the plasma. The sustained antihypertensive effect of this drug seem ed to be due to the slow elimination of M-I from the blood vessels. Wi th daily oral dosing for 14 days, no appreciable amounts of drug-relat ed compounds were accumulated in rat body.