代谢
这项研究的目的/是研究对-甲苯磺酰胺(PTS)在体内和体外的代谢以及其对细胞色素P450酶(CYP450)的影响。在大鼠静脉预处理PTS后,测定总CYP450和微粒体蛋白含量。将CYP特异性底物与大鼠肝脏微粒体一起孵化。通过使用HPLC确定特定CYP同种型的活性。将CYP化学抑制剂添加到孵化混合物中,用于研究参与PTS代谢的主要CYP同种型。通过将PTS与特定底物一起孵化来研究PTS对CYP同种型的影响。分别用33和99毫克/千克/天的PTS处理的组,总CYP含量分别为0.66+/-0.17和0.60+/-0.12纳米摩尔/毫克。K(m)和V(max)分别为92.2微摩尔/升和0.0137纳米摩尔/分钟/毫克蛋白。CYP2C7、CYP2D1和CYP3A2可能在大鼠肝脏中参与PTS的代谢。磺胺苯唑和酮康唑对PTS代谢的抑制效果显示出混合机制,而奎尼丁以非竞争性方式抑制PTS代谢。PTS对所选CYP同种型的活性影响很小。总的来说,PTS与其他药物联合使用相对安全。然而,在给予CYP抑制剂和CYP2C、CYP2D和CYP3A的底物时,应谨慎使用PTS。
/The purpose of this study was/ to study the in vivo and in vitro metabolism and the effect of para-toluene-sulfonamide (PTS) on cytochrome P450 enzymes (CYP450). Total CYP450 and microsome protein content were determined after iv pretreatment of rats with PTS. CYP-specific substrates were incubated with rat liver microsomes. Specific CYP isoform activities were determined by using HPLC. CYP chemical inhibitors added to the incubation mixture were used to investigate the principal CYP isoforms involved in PTS metabolism. The effect of PTS on CYP isoforms was investigated by incubating PTS with specific substrates. The groups treated with 33 and 99 mg/kg per d PTS, respectively, had a total CYP content of 0.66+/-0.17 and 0.60+/-0.12 nmol/mg. The K(m) and V(max) were 92.2 umol/L and 0.0137 nmol/min per mg protein. CYP2C7, CYP2D1 and CYP3A2 might contribute to PTS metabolism in the rat liver. The inhibitory effects of sulfaphenazole and ketoconazole on PTS metabolism were shown to have a mixed mechanism, whereas PTS metabolism was inhibited noncompetitively by quinidine. PTS had little effect on the activities of the selected CYP isoforms. Generally speaking, it is relatively safe for PTS to be co-administered with other drugs. However, care should be taken when administering PTS with CYP inhibitors and the substrates of CYP2C, CYP2D and CYP3A.
来源:Hazardous Substances Data Bank (HSDB)