司巴丁/异喹胍基因多态性对右芬氟拉明代谢的影响。

The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine.

作者信息

Gross A S, Phillips A C, Rieutord A, Shenfield G M

机构信息

Department of Clinical Pharmacology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

出版信息

Br J Clin Pharmacol. 1996 Apr;41(4):311-7. doi: 10.1046/j.1365-2125.1996.03178.x.

DOI:10.1046/j.1365-2125.1996.03178.x

PMID:8730977

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2042591/

Abstract

To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2. Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post-dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3. Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136 +/- 1509 micrograms vs 1986 +/- 792 micrograms; 95% CI of difference 926-3374; P < 0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753 +/- 411 micrograms vs 1626 +/- 444 micrograms). 4. Dexfenfluramine AUC was higher in PMs (677 +/- 348 micrograms l-1 h) than EMs 359 +/- 250 micrograms l-1 h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6 +/- 42.4 l h-1 vs 45.6 +/- 19.5 l h-1; 95% CI of difference 1.2-94.7; P < 0.05). The renal clearance was similar in both phenotypes (EMs: 5.88 +/- 2.83 l h-1; PMs 6.60 +/- 2.01 l h-1), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5. The apparent nonrenal clearance of dexfenfluramine was substantially lower (P < 0.05; 95% CI of difference 3.0-94.1) in PMs (39.0 +/- 19.5 l h-1) than EMs (87.6 +/- 41.2 l h-1). 6. There was a significant inverse correlation (rs = 0.776 95% CI-0.31-0.94; n = 11; p = 0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7. PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8. In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.

摘要

为确定右芬氟拉明是否为细胞色素P450 2D6（CYP2D6）的底物，在9名异喹胍代谢充分者（EM）和8名异喹胍代谢不良者（PM）中对其处置情况进行了研究。2. 给予30 mg盐酸右芬氟拉明后，收集所有受试者给药后96小时的尿液，并收集11名受试者（6名EM和5名PM）的血浆样本。采用高效液相色谱法测定尿液中的右芬氟拉明和去甲右芬氟拉明，采用气相色谱法测定血浆中的右芬氟拉明和去甲右芬氟拉明。3. PM中右芬氟拉明的尿回收率高于EM（4136±1509微克对1986±792微克；差异的95%置信区间为926 - 3374；P<0.05），而去甲右芬氟拉明在两种表型中的回收率相似（PM：1753±411微克对1626±444微克）。4. PM中右芬氟拉明的AUC（677±348微克·升⁻¹·小时）高于EM（359±250微克·升⁻¹·小时）。右芬氟拉明的表观口服清除率在EM中高于PM（93.6±42.4升·小时⁻¹对45.6±19.5升·小时⁻¹；差异的95%置信区间为1.2 - 94.7；P<0.05）。两种表型的肾清除率相似（EM：5.88±2.83升·小时⁻¹；PM：6.60±2.01升·小时⁻¹），这表明PM中右芬氟拉明较高的尿回收率反映了较高的血浆浓度，而非右芬氟拉明在肾脏处理方面的表型差异。5. PM中右芬氟拉明的表观非肾清除率（39.0±19.5升·小时⁻¹）显著低于EM（87.6±41.2升·小时⁻¹）（P<0.05；差异的95%置信区间为3.0 - 94.1）。6. 异喹胍代谢率与右芬氟拉明的表观非肾清除率之间存在显著的负相关（rs = 0.776，95%置信区间 - 0.31 - 0.94；n = 11；p = 0.005）。7. PM中不良反应（恶心和呕吐）的发生率高于EM。8. 总之，PM中右芬氟拉明的代谢受损。因此，异喹胍代谢不良者中缺乏的同工酶CYP2D6必定催化右芬氟拉明生物转化的至少一条途径。