地尔硫对大鼠离体肝脏灌流中安替比林代谢的影响

Inhibitory effect of diltiazem on antipyrine metabolism in the isolated perfused rat liver model

以安替比林（AP）为模型药，采用大鼠离体肝脏灌流模型（IPRL），研究钙离子拮抗剂地尔硫本（DZ）对AP代谢的影响。方法：15只雄性Sprague-Dawley大鼠随机分为3组，A、B组灌胃（iP）生理盐水3d，第4天分别用5mgAP及加用2mgDZ循环灌流3h，C组ipDZ（100·kg-1）3d，第4天同B组灌流。HPLC法测定灌流液中AP及其代谢物的浓度。结果：B、C组中，AP的T1/2从（127．9±9.4）min分别延长至（2742±33.6）和（303.8±80．2）min（P＜0．01）；Cls从（0．67±0.08）ml·min－1分别减少至（0．36±0.06）和（0．34±0．09）ml·min－1（P＜0．01）；4-羟基AP的AUC0-3h分别降低73．95％和68.1％（P＜0．01）；3-羟甲基AP和N-去甲基AP和没有明显变化（P＞0．05）。结论：DZ明显抑制TAP在IPRL中的消除，且选择性地抑制AP的4-羟基化代谢途径。

To investigate the inhibitory effect of diltiazem (DZ) on cytochrome P450 activities by using the isolated perfused rat liver (IPRL) model, and using antipyrin (AP) clearance and metaboite formation as in vivo makers of dihaent P450 isozyme activities. MEIHODS: Prior to perfusion, oral dosing was carried out for 3d on three groups of male Sprague-Dawley rats, in-volving:Pretreatment with water (control and H2O/DZ) or DZ (DZ oral group). On the fouth day, Perfuson experiments took place using techniques, with the adding of 2mg DZ to the H2O/DZ and DZ oral groups, and 5mg M to all groups. Perfusate sam-Ples were assayed by HPLC for AP and its three metaboites. RESULTS: DZ treatment significantly decreased AP clearance from(0.67 ± 0.08) to (0. 36±0.06) (H2O/DZ group) and (0. 34 ±0. 09) (DZ oral group) ml.min- 1 (P＜0.01). The evel of 4-OHAP in both DZ groupo were significantly lower than in control groups(P＜0.01), the level of 3-OHMAP or NorAp in both DZ groups had no wifican change compared with control group (P ＞0.05 ). CONCLUSIONS:AP dipoion and 4-OHAP pnduction had been inhibited by DZ. DZ exhibited selectivity in its inhibitory effect on cytochrome P450 isozymes