Hussain M D, Tam Y K, Gray M R, Coutts R T
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Drug Metab Dispos. 1994 Jul-Aug;22(4):530-6.
The effect of several tertiary amines, which are known enzyme inhibitors, on the disposition of diltiazem (DZ) was evaluated using a single-pass isolated rat liver perfusion system. Coinfusion of lidocaine (LID) or diphenhydramine (DPH) at the steady state of DZ resulted in a sharp increase in the perfusate concentration of DZ, which was followed by a decline to a new steady-state concentration (Cnss) that was higher than the original Cnss value (46 and 45%, respectively). The initial sharp increase in DZ concentration was attributed to the displacement of DZ from its tissue binding sites; the higher Css values were due to the inhibition of N-oxidation and O-demethylation, and some unknown primary metabolic pathways. The kinetics of LID were altered by DZ; the steady-state extraction ratio of LID was reduced and the characteristic maximum in the concentration-time profile of its N-deethylated metabolite, MEGX, was abolished. These results suggest that DZ and LID share common isozymes in their disposition and that the two drugs are also capable of inactivating similar enzymes. The effect of enzyme inactivation on DZ disposition was evaluated by intraperitoneal pretreatment of rats with either saline (0.4 ml) or 1 of the 4 drugs--DZ (20 mg/kg), LID (30 mg/kg), DPH (20 mg/kg), and verapamil (10 mg/kg)--daily for at least 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)
使用单通道离体大鼠肝脏灌注系统，评估了几种已知为酶抑制剂的叔胺对地尔硫䓬（DZ）处置的影响。在DZ达到稳态时共同输注利多卡因（LID）或苯海拉明（DPH），导致DZ灌注液浓度急剧升高，随后下降至高于原始稳态浓度（Cnss）的新稳态浓度（分别升高46%和45%）。DZ浓度最初的急剧升高归因于DZ从其组织结合位点的置换；较高的Css值是由于N - 氧化和O - 去甲基化以及一些未知的主要代谢途径受到抑制。DZ改变了LID的动力学；LID的稳态提取率降低，其N - 去乙基代谢产物MEGX的浓度 - 时间曲线中的特征最大值消失。这些结果表明，DZ和LID在处置过程中共享共同的同工酶，并且这两种药物也能够使相似的酶失活。通过每天给大鼠腹腔内注射生理盐水（0.4 ml）或4种药物之一——DZ（20 mg/kg）、LID（30 mg/kg）、DPH（20 mg/kg）和维拉帕米（10 mg/kg）——至少3天，评估酶失活对DZ处置的影响。（摘要截短于250字）
