摘要
目的研究抗肿瘤新药对甲基苯磺酰胺(PTS)肝代谢过程中对大鼠CYP3A2,CYP2D1,CYP1A2的影响,P-糖蛋白抑制剂对PTS代谢的影响,PTS合并用药时的代谢变化。方法♂Wistar大鼠分组ip苯巴比妥,酮康唑和维拉帕米连续给药3 d后肝灌流PTS 25μmol.L-1,比较空白组与各处理组PTS代谢变化。♂Wistar大鼠分组ip PTS 33和99 mg.kg-1.d-1连续给药4 d后分别肝灌流CYP3A2,CYP2D1底物右美沙芬和CYP1A2底物非那西丁。比较空白组与PTS处理组对CYP3A2,CYP2D1,CYP1A2活性的影响。体外实验右美沙芬40μmol.L-1和非那西丁20μmol.L-1与不同浓度的PTS在空白微粒体中温孵。PTS与不同浓度依托泊苷(VP-16),氟尿嘧啶(5-FU)在空白微粒体中温孵。结果苯巴比妥诱导组PTS代谢加快,酮康唑组代谢减慢。右美沙芬和非那西丁代谢在温孵反应中与空白组无显著差别。依托泊苷体外实验中抑制PTS代谢达50.7%,氟尿嘧啶对PTS代谢没有影响。结论大鼠原位肝灌流是良好的整体器官药物代谢模型,是体外实验有力的补充。PTS大鼠肝代谢与CYP450相关。PTS代谢不影响CYP3A2,CYP2D1,CYP1A2活性。P-糖蛋白抑制剂不影响PTS在实验条件下的代谢。合并用药的依托泊苷对PTS肝代谢有显著抑制。
OBJECTIVE To investigate the influence of novel anticancer drug para toluene sulfonamide（PTS） on CYP3A2, CYP2D1, CYP1A2 activities, P-gp, and drug interactions in rats. METHODS Male Wistar rats were pretreated with ip phenobarbital （PB）, ketoconazole（Ket）, verapamil（Ver） for 3 d and in situ rat liver perfusion in a recirculation system was conducted for 1 h with PTS preparation; Male Wistar rats were pretreated with ip PTS 33 and 99 mg·kg^-1·d^-1 for 4 d and dextromethorphan （Dex） and phenacetin （Phe） liver perfusions were conducted.Different concentrations of PTS were incubated with Dex and Phe in microsome; Different concentrations of VP-16 and 5-FU were incubated with PTS in microsome.RESULTS The metabolism of PTS was induced in PB-treated group and inhibited in ket-treated group. No metabolism difference between control and Dex/Phe treated groups was found. VP-16 inhibited PTS metabolism by 50.7% compared with negative control, while 5-FU had no influential effect. CONCLUSION In situ liver peffusion is an appropriate organ model for drug metabolism and disposition research. Liver CYP450 is responsible for PTS metabolism. PTS rat liver metabolism has no influential effect to CYP3A2, CYP2D1, CYP1A2 activities. P-glycoptotein inhibited by Ver has no significant effect on PIS metabolism at the experiment conditions. VP-16 has inhibitory impact on PIS which need more investigation in clinical use.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2006年第8期615-618,626,共5页
Chinese Pharmaceutical Journal
基金
北京市教委科研基金(KM200410025007)
作者简介
周江泉,女,硕士研究生
通讯作者：张锦楠,女,教授 Tel：（010）83911517 E-mail：zhoujiangquan@gmail.com
