Abstract
Debrominated derivative of bromobutide labeled at carbonyl carbon ([carbonyl-14C] N-(1-methyl-1-phenylethyl)-3, 3-dimethylbutanamide, 14CO-deBr-bromobutide) was orally administered to seven-week old male S. D. rats and ICR mice and the fates of the compound were investigated to compare with those of bromobutide. In rats, deBr-bromobutide was rapidly hydroxylated at phenyl and t-butyl groups, and excreted quantitatively. 14CO-deBr-Bromobutide treatments gave faster 14C elimination, higher urinary excretion, and lower 14C residue levels in tissues and contents of intestinal tract compared with 14CO-bromobutide administration. deBr-Bromobutide was a better substrate for ω-hydroxylation than bromobutide in a microsomal suspension of rat liver with NADPH, but was a poor substrate for aromatic hydroxylation as bromobutide in in vitro assay. Major metabolites of deBr-bromobutide and bromobutide in rats were glucuronides of the alcohol and phenol derivatives and underwent enterohepatic circulation. Glucuronides of alcohol derivatives (major products) from deBr-bromobutide exhibited faster urinary excretion after conversion to carboxylic acids, while phenol type glucuronides (major metabolites) from bromobutide was retained slightly longer in the body. Mice had higher activities of hydroxylation, especially at the phenyl group and threshold value of higher molecular weight for biliary excretion than rats so as to give faster metabolism and higher urinary excretion for both compounds. It was concluded that although there were some species differences and substrate specificities for enzymatic hydroxylation, deBr-bromobutide behaved in quite a similar way as bromobutide did and that the metabolic pathway established for deBr-bromobutide from the identification of metabolites was, in turn, involved in the identification of bromobutide in mammals.
