Pharmacokinetics of 5-(4-(2-Carboxyethylcarbamoyle)-phenylazo) Salicylic Acid Disodium Salt Dihydrate (BX661A). (3): Distribution and Excretion in Rat after Single Oral and Intravenous Administration.

Abstract

The distribution and excretion of radioactivity, and of the unchanged drug and major metabolites were investigated in rats after a single oral or intravenous administration of 14C-BX661A (labeled at 5ASA moiety: 14C-BX661A (5ASA), labeled at 4ABA moiety: 14C-BX661A (4ABA)) and non-labeled BX661A. 1. After oral administration of 14C-BX661A(5ASA) to fasted male rats, the radioactivity reached the highest level at 10 hr after administration in most tissues, except gastrointestinal tract. At this time point, the tissues showing higher level of radioactivity than that in plasma, were liver and kidney, except gastrointestinal tract. After administration of 14C-BX661A (4ABA), similar results were obtained. However, the levels of radioactivity were lower than those of 14C-BX661A (5ASA). 2. During 72 hr after oral administration of 14C-BX661A (5ASA) to fasted male rats, about 32 and 66% of the dose were excreted into the urine and feces, respectively. In female rats, about 45 and 55% of the dose were excreted into the urine and feces, respectively. While in 14C-BX661A (4ABA), the excretion of radioactivity into the urine and feces were about 7 and 88% of the dose in male rats, and the similar results were obtained in female rats. 3. During 72 hr after oral administration of BX661A to fasted male rats at a dose of 50, 100 and 200 mg/ kg, the excretion of the unchanged drug into the urine and feces were less than 0.6% of the dose. It was suggested that azo linkage of BX661A was almost completely cleavaged. Urinary excretion of 5ASA and Ac-5ASA accounted for 0.0-2.2% and 21.1-24.5%, and fecal excretion were 22.7-25.3% and 20.0-32.1% of the dose, respectively. On the other hand, urinary excretion of 4ABA and Ac-4ABA were less than 0.8 and 3.4-4.3% of the dose, respectively. Fecal excretion of 4ABA and Ac-4ABA were 67.3-78.5% and 2.7-5.1% of the dose, respectively. 4. During 72 hr after oral administration of BX661A to fasted female rats at a dose of 100 mg/kg, the fecal excretion of Ac-5ASA was significantly higher than those of male. Excretion pattern of another compounds were similar to those of male rats. 5. During 72 hr after intravenous administration of 14C-BX661A(5ASA) to fasted male rats, about 43 and 55% of the dose were excreted into the urine and feces, respectively. After administration of 14C-BX661A (4ABA), about 29 and 66% of the dose were excreted into the urine and feces, respectively. After intravenous administration of BX661A to fasted male rats, 29.5% of the dose was excreted into the urine as the unchanged drug within 8 hr. On the other hand, urinary excretion of Ac-5ASA was 11.5%, and fecal excretions of 5ASA, Ac-5ASA and 4ABA were 4.9, 19.3 and 29.0% of the dose during 72 hr, respectively. 6. After oral administration of 14C-BX661A to fasted male rats, the biliary excretions within 24 hr were 3-4% of the dose in both labeled compounds. After intravenous administration of 14C-BX661A (5ASA) to fasted male and female rats, the biliary excretion within 120 min was low in male rats compared with female (male: 67%, female: 80%). 7. Azo-bond of BX661A was easily reduced by reacting with human feces. After 90 min of reaction, the unchanged drug was not detected and the formation of 5ASA was observed. However, Ac-5ASA was not detected in the reaction mixture.