Moghadamnia A A, Rostami-Hodjegan A, Abdul-Manap R, Wright C E, Morice A H, Tucker G T
Molecular Pharmacology & Pharmacogenetics, Division of Clinical Sciences (South), University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.
Br J Clin Pharmacol. 2003 Jul;56(1):57-67. doi: 10.1046/j.1365-2125.2003.01853.x.
To define the relative antitussive effect of dextromethorphan (DEX) and its primary metabolite dextrorphan (DOR) after administration of DEX.
Data were analysed from a double-blind, randomized cross-over study in which 22 subjects received the following oral treatments: (i) placebo; (ii) 30 mg DEX hydro-bromide; (iii) 60 mg DEX hydro-bromide; and (iv) 30 mg DEX hydro-bromide preceded at 1 h by quinidine HCl (50 mg). Cough was elicited using citric acid challenge. Pharmacokinetic data from all non-placebo arms of the study were fitted simultaneously. The parameters were then used as covariates in a link PK-PD model of cough suppression using data from all treatment arms.
The best-fit PK model assumed two- and one-compartment PK models for DEX and DOR, respectively, and competitive inhibition of DEX metabolism by quinidine. The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l x h(-1), which overlapped with that extrapolated from in vitro data (12-261 l x h(-1)) and showed similar variation (26- vs. 21-fold, respectively). The inhibitory effect of quinidine ([I]/Ki) was 19 (95% confidence interval of mean: 18-20) with an estimated average Ki of 0.017 microM. Although DEX and DOR were both active, the potency of the antitussive effect of DOR was 38% that of DEX. A sustained antitussive effect was related to slow removal of DEX/DOR from the effect site (ke0 = 0.07 h(-1)).
Physiologically based PK modelling with perturbation of metabolism using an inhibitor allowed evaluation of the antitussive potency of DOR without the need for separate administration of DOR.
确定右美沙芬（DEX）给药后其主要代谢产物右啡烷（DOR）的相对镇咳作用。
对一项双盲、随机交叉研究的数据进行分析，22名受试者接受以下口服治疗：（i）安慰剂；（ii）30mg氢溴酸右美沙芬；（iii）60mg氢溴酸右美沙芬；（iv）在服用30mg氢溴酸右美沙芬前1小时先服用50mg盐酸奎尼丁。采用柠檬酸激发引发咳嗽。对研究中所有非安慰剂组的药代动力学数据进行同步拟合。然后将这些参数用作协变量，采用所有治疗组的数据建立咳嗽抑制的PK-PD链接模型。
最佳拟合PK模型分别假定DEX和DOR的药代动力学模型为二室和一室模型，以及奎尼丁对DEX代谢的竞争性抑制。根据模型估计的DEX内在清除率范围为59至1536 l×h⁻¹，与从体外数据推断的值（12至261 l×h⁻¹）重叠，且显示出相似的变化（分别为26倍和21倍）。奎尼丁的抑制作用（[I]/Ki）为19（平均95%置信区间：18至20），估计平均Ki为0.017μM。虽然DEX和DOR均有活性，但DOR的镇咳作用效力为DEX的38%。持续的镇咳作用与DEX/DOR从效应部位的缓慢清除有关（ke0 = 0.07 h⁻¹）。
基于生理学的PK建模结合使用抑制剂对代谢进行扰动，无需单独给予DOR即可评估DOR的镇咳效力。
