Gee S J, Green C E, Tyson C A
Drug Metab Dispos. 1984 Mar-Apr;12(2):174-8.
Tolbutamide (TB; 1-butyl-3-p-tolylsulfonylurea) was used for metabolism studies with hepatocytes isolated from the rat, rabbit, dog, and squirrel monkey to validate their usefulness as models for comparative in vivo metabolism. Hepatocytes were prepared by whole liver or biopsy perfusion. TB (3 X 10(-4) M) was metabolized by each of the preparations over a 4-hr incubation period at rates ranging from 175.8 to 9.2 pmol/10(6) cells/min with the rates from hepatocytes from: rat greater than rabbit much greater than squirrel monkey greater than dog. The metabolite profiles determined in extracts of hepatocyte suspensions after 4 hr of incubation showed marked species differences. The major metabolite for the rat and squirrel monkey was 1-butyl-3-p-hydroxy-methylphenylsulfonylurea (73.2 and 46.7% of total metabolites, respectively). p-Tolylsulfonylurea and p-tolylsulfonamide were the major metabolites found in the dog (44.1 and 40.2%, respectively). Rabbit hepatocytes formed mostly 1-butyl-3-p-carboxyphenylsulfonylurea (63.9%). Both the relative rates of metabolism and the metabolite profiles from hepatocytes from the rat, rabbit, and dog correlated well with published in vivo data on TB plasma half-lives and urinary metabolite profiles. These results suggest that isolated hepatocytes may have utility as in vitro models for comparative in vivo metabolism.
甲苯磺丁脲（TB；1-丁基-3-对甲苯磺酰脲）用于对从大鼠、兔子、狗和松鼠猴分离出的肝细胞进行代谢研究，以验证它们作为体内比较代谢模型的有效性。肝细胞通过全肝或活检灌注制备。在4小时的孵育期内，每种制备物对TB（3×10⁻⁴M）的代谢速率在175.8至9.2皮摩尔/10⁶个细胞/分钟之间，其中大鼠肝细胞的代谢速率＞兔子肝细胞的代谢速率＞＞松鼠猴肝细胞的代谢速率＞狗肝细胞的代谢速率。孵育4小时后，肝细胞悬液提取物中测定的代谢物谱显示出明显的物种差异。大鼠和松鼠猴的主要代谢物是1-丁基-3-对羟基甲基苯磺酰脲（分别占总代谢物的73.2%和46.7%）。对甲苯磺酰脲和对甲苯磺酰胺是在狗中发现的主要代谢物（分别为44.1%和40.2%）。兔肝细胞主要形成1-丁基-3-对羧基苯磺酰脲（63.9%）。大鼠、兔子和狗肝细胞的相对代谢速率和代谢物谱与已发表的关于TB血浆半衰期和尿代谢物谱的体内数据相关性良好。这些结果表明，分离的肝细胞可能作为体内比较代谢的体外模型具有实用性。
