title: The biotransformation of sulfadimethoxine, sulfadimidine, sulfamethoxazole, trimethoprim and aditoprim by primary cultures of pig hepatocytes.
abstract: The in vitro biotransformation of three sulfonamides, trimethoprim and aditoprim, was studied using primary cultures of pig hepatocytes. Incubation of monolayer cultures with sulfadimethoxine (SDM), sulfamethoxazole (SMX) and 14C-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 acetylsulfonamides to the cells showed that these compounds were deacetylated, each to a different extent. A relatively low degree of acetylation (in the case of SDD) was paralleled by extensive deacetylation (i.e. AcSDD), whereas extensive acetylation (i.e. SMX) was in concert with minor deacetylation (i.e. AcSMX). The addition of bovine serum albumin to the medium resulted in a decrease in conversion of sulfonamides as well as acetylsulfonamides. The main metabolic pathway of 14C-trimethoprim (TMP) was O-demethylation with subsequent conjugation. Two hydroxy (demethyl) metabolites were formed, namely 3'- and 4'-demethyl trimethoprim, which were both glucuronidated while 3'-demethyl trimethoprim was also conjugated with sulphate. The capacity to form conjugates with either glucuronic acid or sulphate was at least as high as the capacity for O-demethylation since more than 90% of the metabolites were excreted as conjugates in the urine of pigs. Addition of 14C-aditoprim (ADP) to the hepatocytes led to the N-demethylation of ADP to mono-methyl-ADP and didesmethyl-ADP. During the incubation another three unknown ADP metabolites were formed. In contrast to TMP, no hydroxy metabolites or conjugated metabolites of aditoprim were formed. These in vitro results were in agreement with the in vivo biotransformation pattern of the studied sulfonamides and trimethoprim in pigs.
authors.affiliation: State Institute for Quality Control of Agricultural Products (RIKILT-DLO), Department of Risk Assessment & Toxicology, Wageningen, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Mengelers
authors.forename: G A
authors.initials: GA
authors.lastname: Kleter
authors.forename: L A
authors.initials: LA
authors.lastname: Hoogenboom
authors.forename: H A
authors.initials: HA
authors.lastname: Kuiper
authors.forename: A S
authors.initials: AS
authors.lastname: Van Miert
mesh_terms: D000107:Acetylation; D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000662:veterinary; D005260:Female; D005493:Folic Acid Antagonists / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008745:Methylation; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013412:Sulfadimethoxine / Q000378:metabolism / Q000494:pharmacology; D013418:Sulfamethazine / Q000378:metabolism / Q000494:pharmacology; D013420:Sulfamethoxazole / Q000378:metabolism / Q000494:pharmacology; D013552:Swine; D014295:Trimethoprim / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D005493:Folic Acid Antagonists; C051398:aditoprim; D013412:Sulfadimethoxine; D013418:Sulfamethazine; D014295:Trimethoprim; D013420:Sulfamethoxazole