THE BIOTRANSFORMATION OF SULFADIMETHOXINE, SULFADIMIDINE, SULFAMETHOXAZOLE, TRIMETHOPRIM AND ADITOPRIM BY PRIMARY CULTURES OF PIG HEPATOCYTES

The in vitro biotransformation of three sulfonamides, trimethoprim and aditoprim, was studied using primary cultures of pig hepatocytes. Inc ubation of monolayer cultures with sulfadimethoxine (SDM), sulfamethox azole (SMX) and C-14-sulfadimidine (SDD) resulted in the formation of the corresponding N4-acetylsulfonamide to different extents, depending upon the molecular structure of the drug. Addition of the acetylsulfo namides to the cells showed that these compounds were deacetylated, ea ch to a different extent. A relatively low degree of acetylation (in t he case of SDD) was paralleled by extensive deacetylation (i.e. AcSDD) , whereas extensive acetylation (i.e. SMX) was in concert with minor d eacetylation (i.e. AcSMX). The addition of bovine serum albumin to the medium resulted in a decrease in conversion of sulfonamides as well a s acetylsulfonamides. The main metabolic pathway of C-14-trimethoprim (TMP) was O-demethylation with subsequent conjugation. Two hydroxy (de methyl) metabolites were formed, namely 3'- and 4'-demethyl trimethopr im, which were both glucuronidated while 3'-demethyl trimethoprim was also conjugated with sulphate. The capacity to form conjugates with ei ther glucuronic acid or sulphate was at least as high as the capacity for O-demethylation since more than 90% of the metabolites were excret ed as conjugates in the urine of pigs. Addition of C-14-aditoprim (ADP ) to the hepatocytes led to the N-demethylation of ADP to mono-methyl- ADP and di-desmethyl-ADP. During the incubation another three unknown ADP metabolites were formed. In contrast to TMP, no hydroxy metabolite s or conjugated metabolites of aditoprim were formed. These in vitro r esults were in agreement with the in vivo biotransformation pattern of the studied sulfonamides and trimethoprim in pigs.