Mengelers M J, Kleter G A, Hoogenboom L A, Kuiper H A, Van Miert A S
State Institute for Quality Control of Agricultural Products (RIKILT-DLO), Department of Risk Assessment & Toxicology, Wageningen, The Netherlands.
J Vet Pharmacol Ther. 1997 Feb;20(1):24-32. doi: 10.1046/j.1365-2885.1997.00048.x.
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.
利用猪肝细胞原代培养物研究了三种磺胺类药物、甲氧苄啶和阿地普明的体外生物转化。用二甲氧苄氨嘧啶（SDM）、磺胺甲恶唑（SMX）和14C - 磺胺嘧啶（SDD）对单层培养物进行孵育，根据药物的分子结构，会不同程度地形成相应的N4 - 乙酰磺胺。向细胞中添加乙酰磺胺表明这些化合物会发生去乙酰化，且每种化合物的去乙酰化程度不同。相对较低程度的乙酰化（如SDD的情况）伴随着广泛的去乙酰化（即AcSDD），而广泛的乙酰化（即SMX）则伴随着较小程度的去乙酰化（即AcSMX）。向培养基中添加牛血清白蛋白会导致磺胺类药物以及乙酰磺胺的转化率降低。14C - 甲氧苄啶（TMP）的主要代谢途径是O - 去甲基化并随后进行结合。形成了两种羟基（去甲基）代谢产物，即3'-和4'-去甲基甲氧苄啶，它们都与葡糖醛酸结合，而3'-去甲基甲氧苄啶还与硫酸盐结合。与葡糖醛酸或硫酸盐形成结合物的能力至少与O - 去甲基化能力一样高，因为超过90%的代谢产物在猪尿中以结合物形式排出。向肝细胞中添加14C - 阿地普明（ADP）会导致ADP发生N - 去甲基化生成单甲基 - ADP和双去甲基 - ADP。在孵育过程中还形成了另外三种未知的ADP代谢产物。与TMP不同，阿地普明没有形成羟基代谢产物或结合代谢产物。这些体外实验结果与猪体内所研究的磺胺类药物和甲氧苄啶的生物转化模式一致。
