阿苯达唑及其代谢物在欧洲鳗鲡体内的药代动力学及残留研究

在试验水温（25±2）℃条件下,按2 mg/kg的浓度给欧洲鳗鲡浸浴阿苯达唑36 h,高效液相色谱法测定血浆和肌肉组织中的药物浓度,研究阿苯达唑在欧洲鳗鲡体内的代谢及消除规律。结果显示：阿苯达唑和阿苯达唑亚砜的血药时间数据符合一级吸收二室开放模型,阿苯达唑砜符合一级吸收一室开放模型;其消除半衰期分别为34.15h、99.34h、46.00 h,最大血药浓度分别为3.887、6.830、1.738 mg/L,达峰时间分别为7.27h1、8.00h、40.67h,药时曲线下面积（AUC）分别为129.71、921.95、236.58 mg.h/L。选取可食组织肌肉作为残留检测的靶组织,以农业部残留限量100μg/kg为最高残留限量,在本试验条件下,建议休药期不低于23 d。     

A UK analysis of the cost of switching renal transplant patients from an immediate-release to a prolonged-release formulation of tacrolimus based on differences in trough concentration variability

Background and aims:

Randomized controlled trials have shown that a once-daily prolonged-release (PR) tacrolimus formulation (PR tacrolimus; Advagraf), is non-inferior to a twice-daily immediate-release (IR) tacrolimus formulation (IR tacrolimus; Prograf) in terms of biopsy-proven acute rejection, graft failure and mortality in renal transplant recipients. However, relative to IR tacrolimus, PR tacrolimus exhibits reduced tacrolimus trough concentration variability, which has been associated with reduced graft failure. Based on these data, the present study evaluated the cost of switching UK renal transplant patients from IR tacrolimus to PR tacrolimus.

Methods:

UK-specific data on acute rejection, graft failure, and mortality were used to construct a budget impact model to assess the costs of switching from IR tacrolimus to PR tacrolimus on a 1:1?mg:mg basis. The model assumed that 3.1% of patients on PR tacrolimus had high tacrolimus trough concentration variability compared with 17.4% on IR tacrolimus, based on a study comparing PR tacrolimus and IR tacrolimus pharmacokinetics. A relative graft failure risk of 2.38 was applied to high variability patients based on data from a tacrolimus variability study in which 10/148 patients with low variability experienced graft failure, compared with 24/149 in the high variability group. Cost data were taken from the British National Formulary and 2012–2013 NHS tariff information.

Results:

The mean per-patient cost (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was GBP 26,941 (standard deviation [SD]?=?GBP 2765) with PR tacrolimus vs GBP 30,356 (SD?=?GBP 3085) for IR tacrolimus over a 5-year period, corresponding to a saving of GBP 3415 (SD?=?GBP 516) per patient or GBP 341,500 in a hypothetical 100-patient transplant center. Cost savings were driven primarily by lower dialysis costs resulting from the lower proportion of PR tacrolimus patients with high tacrolimus trough concentration variability (leading to lower graft failure risk).

Limitations:

The main limitation of the study was the use of heterogeneous data sources to capture the effect of within-patient variability on graft failure. The most important difference between the studies was the definition of the threshold between low and high within-patient variability. This was explored in sensitivity analyses in which the inter-arm difference in the inter-arm proportions of patients with high and low variability was abolished.

Conclusions:

Converting UK renal transplant recipients from IR tacrolimus to PR tacrolimus was associated with lower pharmacy and dialysis costs.     

伊曲康唑对合用药物药代动力学的影响机制初探

目的探讨伊曲康唑对合用药物药代动力学的影响机制,为临床上安全合理地利用合成药物提供依据。方法利用健康成人的肝细胞微粒体,将其分为加入不同浓度伊曲康唑的10个小组,浓度梯度为0.0、0.4、0.8、1.6、3.2μg/ml,每组做5个平行组,之后在其中五组加入肝细胞微粒体细胞色素的P450的同功酶1A2的底物非那西丁,在另外五组中加入同工酶3A4的底物睾酮,测量不同伊曲康唑下的同功酶1A2和3A4的相对活性。结果各浓度伊曲康唑组对同功酶1A2作用效果无明显差异,各浓度伊曲康唑组对同功酶3A4的作用较明显,同功酶3A4的活性随着伊曲康唑的浓度增大而减小,其减小到本实验的最大活性一半时的伊曲康唑的浓度为0.7μg/ml。结论伊曲康唑对健康成年人肝细胞微粒体细胞色素酶同功酶1A2的活性无显著影响;但是它对同功酶3A4的活性有明显抑制作用,极大地影响了同功酶3A4对合用药物药代动力学的各种参数。     

阿奇霉素在小儿肺炎中的药代学研究

目的探讨阿奇霉素在小儿肺炎中的药代学特征,据此拟订其用于肺炎患儿的给药方案。方法 100例肺炎患儿口服阿奇霉素(10mg/kg)后,以高效液相色谱法(HPLC)测定患儿体内的血药浓度,采用AIC法结合F检验判别房室模型,DAS药动学程序计算药动学参数。结果药代学符合二室模型(Wi=1/C2,AIC=-7.0296),主要药动学参数为:α=(0.31±0.07)/h,β=(0.05±0.01)/h,Ka=(0.76±0.18)/h,t1/2β=(42.37±9.23)/h,tmax=(4.13±0.62)/h,Cmax=(318.72±36.51)μg/L,AUC0-144=(22.38±3.14)μg·h/ml,AUC0-∞=(24.66±3.27)μg·h/ml。结论肺炎患儿口服阿奇霉素后有典型的药代学特征,对指导临床给药具有重要的意义。     

磺胺嘧啶在欧洲鳗鲡体内的药代动力学研究

在（25±1）℃水温条件下,以300 mg/kg的单剂量,给欧洲鳗鲡混饲口灌磺胺嘧啶后,用高效液相色谱法测定血浆和肌肉中的药物浓度,研究了磺胺嘧啶在欧洲鳗鲡体内的药代动力学特征。结果表明：欧洲鳗鲡血浆和肌肉中磺胺嘧啶经时过程均符合一级吸收二室开放模型,其理论方程为：C血浆=196.16^e-0.0308 t＋44.028e^-0.0067 t-7.9584e^-0.0871 t,血浆中药物主要动力学参数如下：T1/2ka为7.9584h;T1/2a为22.473h;T1/2β为104.27h;Tmax为21.512h;Cmax为100.51mg/L。C肌肉=0.077e^-0.061 t＋34.545e^-0.015 t-3.8399e^-0.181 t,肌肉中主要动力学参数如下：T1/2ka为3.8399h;T1/2a为11.277h;T1/2β为46.210h;Tmax为15.762h;Cmax为25.024mg/kg。以20μg/kg为最高残留限量计算,在本试验条件下,建议磺胺嘧啶在欧洲鳗鲡体内的休药期不低于48d。