Studies on the metabolic fate of Benazepril hydrochloride in rats (I) : Plasma level profile, distribution, metabolism and excretion after single administration.

Abstract

The absorption, distribution, excretion and metabolism of CGS 14824 A were studied in rats after single administration of ¹⁴C-CGS 14824 A and ¹⁴C-CGS 14831.
1. After oral administration of ¹⁴C-CGS 14824 A at dose of 3mg/kg to fasting male rats, the radioactivity in the plasma reached C_max of 1993ng eq./ml at 10min and the elimination half-lives were 0.37hr (20min ?? 2hr) and 10hr (4 ?? 12hr). In the case of non-fasting male rats, the time of Cmax was delayed by 20min and the level was reduced to 529ng eq./ml ; AUC was not altered by food. Plasma radioactivity increased in proportion to the administered dose with C_max and AUC between 1mg/kg and 10mg/kg. The sex-related differences in the pharmacokinetic profile were not observed.
2. After intravenous or oral administration of ¹⁴C-CGS 14824 A, the extent of absorption was about 100%, but that of ¹⁴C-CGS 14831 was about 6 %.
3. Radioactivity was rapidly and widely distributed to tissues, reaching maximum levels at 10min in most tissues after oral administration of ¹⁴C-CGS 14824 A. A high level of radioactivity was observed in the gastrointestinal tract, followed by liver, kidney and bladder. At 6hr, a high level of radioactivity was found in the lung, exceeding 52 times corresponding plasma levels. At 72hr, the level of radioactivity was reduced in all tissues. Similar distribution characteristic were observed with whole body autoradiography.
4. After oral administration of 3mg/kg of ¹⁴C-CGS 14824 A to fasting male rats, the radioactivity was excreted within 24hr accounted for 27.9 and 68.9% of the dose in urine and feces, respectively, and the total excretion was 99.3% within 72hr. The characteristics of excretion was not changed by administration route, dose and sex. After oral administration to non-fasting male rats, excretion in urine was increased to 37.9% at 72hr.
5. Biliary excretion of radioactivity was 55.8% within 24hr after oral dosing, but entero-hepatic circulation was small.
6. The radioactivity in plasma, lung, liver and kidney was comprised mainly of CGS 14831. Compositions were similar in urine, feces and bile.