UGT1A9多态性对丙泊酚靶控输注药效学及单次注射药动学的影响
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摘要
研究背景及目的
丙泊酚(propofol)是一临床应用广泛的速效强效静脉麻醉镇静药物,其具有诸多优点：诱导迅速平稳、体内代谢速度快、停药后苏醒快、安全范围较大、不良反应少等,已经成为全球用量最大的成人临床麻醉和ICU镇静的静脉麻醉药。但文献报道其镇静效应及药代动力学存在较大的个体差异,代谢酶等遗传因素的改变可以影响药物的药代动力学及药效动力学,而镇静药物临床镇静效应的个体差异可能就是受其代谢酶基因多态性的影响。本研究的目的是分析尿苷二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyl tansferase, UGTs)基因1A9多态性对良性乳腺肿块切除术女性患者停止靶控输注丙泊酚后,患者意识恢复期丙泊酚镇静效应个体差异的影响,以及对单次静脉注射丙泊酚后药代动力学的影响,为临床麻醉提供合理的用药方案,为实现以基因为导向的个体化用药提供实验依据。
方法
1.研究对象与分组
选择150例于郑州大学第一附属医院择期行良性乳腺肿块切除手术女性患者,ASA分级：I或Ⅱ级,年龄在20-50岁之间,体重指数范围(1±20%)。术前常规检查心、肝、肺、肾功能均无异常,排除标准：有吸烟史、酗酒史、精神病及癫痫病史、糖尿病、甲亢、内分泌功能紊乱、严重心血管系统疾病、肾脏病、肝脏病史、近期使用过肝药酶诱导剂或抑制剂、长期服用镇静催眠药物的患者。根据UGT1A9基因型检测结果将患者分为野生型纯合子、突变型杂合子和突变型纯合子三组。此研究设计方案通过了郑州大学第一附属医院伦理委员会的批准,患者了解本试验过程并均签署知情同意书后纳入该试验。
2.麻醉方法
2.1药效学部分
本试验中纳入的所有患者均采用统一的静脉麻醉方法,丙泊酚应用靶控输注(TCI)给药模式,麻醉诱导：丙泊酚TCI血浆靶控浓度为3μg/ml,待患者意识消失后静脉注射瑞芬太尼和顺式阿曲库铵,置入喉罩并机械通气；麻醉维持：术中所有患者均以丙泊酚血浆靶控浓度3μg/ml,持续静脉输注瑞芬太尼和间断静脉注射顺式阿曲库铵；在手术结束前30min和5min分别停用顺式阿曲库铵和瑞芬太尼,手术结束即刻停止丙泊酚的靶控输注,同时静脉注射阿托品和新斯的明进行肌松药的拮抗,并对患者进行丙泊酚镇静效应的评估,待患者神志清醒并且自主呼吸恢复良好后拔除喉罩。
2.2药动学部分
所有患者采用统一的全凭静脉麻醉方法,麻醉诱导：30例患者于20s内恒速静脉推注丙泊酚2mg-kg-1、瑞芬太尼1.5μg·kg-1、顷阿曲库铵0.15μg·kg-1待患者意识消失并且肌肉松弛良好后,置入喉罩进行机械通气管理,维持患者的呼气末二氧化碳分压在35-45mmHg范围内波动；麻醉维持：持续吸入1%～2%七氟烷,持续输注瑞芬太尼0.2～0.3μg·kg-1,依麻醉深浅随时调整维持麻醉药物剂量以确保所有患者术中生命体征平稳。术毕及时停药和进行肌松药的拮抗。检测患者UGT1A9基因型,分别分为UGT1A91399C/C(野生型纯合子)I399C/T(突变型杂合子)1399T/T(突变型纯合子)；-1818T/T(野生型纯合子)-1818C/T(突变型杂合子)-1818C/C(突变型纯合子)；-1887T/T(野生型纯合子)-1887T/G(突变型杂合子)-1887G/G(突变型纯合子)。
3.丙泊酚镇静效应的评价
评估并记录停止靶控输注丙泊酚至患者警觉-镇静评分(OAA/S)达到4分的时间、效应室浓度和BIS值,患者意识恢复时(BIS>80)的时间和效应室浓度,以此作为评价停止丙泊酚靶控输注后意识恢复期患者镇静效应的指标。
4.基因型检测
术前采集患者静脉血样1ml,于一周内应用DNA提取试剂盒提取患者的基因组DNA,而后采用聚合酶链反应(polymerase chain reaction, PCR)及直接测序技术,对UGT1A9I399C>T、-1818T>C、-1887T>G多态性位点进行检测分析。
5.血标本采集
药效学部分,停止丙泊酚靶控输注后,于患者BIS升至80时经对侧肘静脉抽取血样3ml,药动学部分,于丙泊酚单次静脉注射后采集患者血样,采血时间分别为：1、3、5、10、15、30、45、60、90、120、240和360min经给药对侧肘静脉抽取血样3ml,EDTA抗凝后3000r/min离心10min,抽取上层血浆2ml保存在EP管内,冻存于-80℃冰箱待测,采用高效液相色谱荧光法检测血浆中的丙泊酚浓度。本实验应用由中国药理学会专业委员会编制的DAS药动学软件处理丙泊酚血药浓度-时间数据,选择最佳房室模型,绘制曲线并求得药动学参数。
统计学分析
采用SPSS17.0软件分析本研究的实验数据,以均数士标准差(x±s)表示计量资料,以x2检验检测等位基因和基因型分布是否符合Hardy-Weinberg平衡；x2检验或Fisher's精确概率法检测不同种族间基因多态性的分布差异；采用单因素方差分析(ANOVA)多组间数据,采用LSD法用于各组间比较。为排除混杂因素的影响,代谢酶不同基因型组间丙泊酚镇静效应的比较采用协方差分析。采用x2检验或Fisher's精确概率法比较各组间不良反应发生率。采用直线相关分析来分析计量资料变量之间的关系。采用直线相关与回归进行处理丙泊酚标准曲线回归方程,检验水准a=0.05。
结果
1.一般情况
纳入本实验的各组患者的年龄、BMI、麻醉时间、手术时间、相关麻醉药品的使用量、术中失血量、输液量、肝肾功能等实验室检查结果等指标组间比较差异均无统计学意义(P>0.05)。
2.乳腺良性肿块患者中UGT1A9等位基因频率
在中国汉族乳腺手术患者UGT1A91399C>T、-18181>C、-18871>G等位基因频率分别为52.3%、41%和9.3%,其等位基因和基因型分布符合Hardy-Weinberg平衡(P>0.05)。其中,UGT1A91399C>T等位基因频率与文献报道的中国汉族(55.0%)无差异(P>o.05),但比日本人群(64.4%)低,比高加索人(38%)高,差别均有统计学意义(P<0.05)。UGT1A9-1818T>C、-18871>G等位基因频率与文献报道的中国汉族(47.6%和9.5%)无差异(P>o.05)。
3.乳腺良性肿块患者丙泊酚TCI药效指标存在较大差异.
本研究结果显示,患者意识恢复期丙泊酚的镇静效应存在较大的个体差异,停止靶控输注丙泊酚至患者OAA/S达到4分的时间5(3,7)min相差18倍,效应室浓度102～209μg·ml-1(2.2±0.4μg·ml-1)相差2.5倍,BIS值51～80(69±7)相差1.9倍；患者BIS>80的时间8(6,11)min相差15倍,效应室浓度0.9-2.8μg·ml-1(1.9±0.4μg-ml-1)相差3.3倍。患者意识恢复期丙泊酚的各项镇静效应指标的最大值和最小值之间呈现较大的个体差异。
4.UGT1A9多态性对乳腺良性肿块患者丙泊酚镇静效应的影响
所有患者根据UGT1A9I399C>T、-1818T>C、-1887T>G基因型检测结果分为野生纯合子组、突变杂合子组和突变纯合子组。一般情况比较各组件差异无统计学意义(P>0.05)；各组间患者肝肾功能等实验室检查结果比较差异均无统计学意义(P>0.05)；停止靶控输注丙泊酚后患者意识恢复期各丙泊酚镇静效应指标在UGT1A9I399C>T、-1818T>C、-1887T>G各基因型组间比较差异无统计学意义(p>0.05)；将患者的年龄、BMI和手术时间作为协变量对实验结果进行协方差分析后的结果表明丙泊酚镇静效应各基因组间差异无统计学意义(P>0.05)；停止靶控输注丙泊酚后患者意识恢复期丙泊酚镇静效应指标,与UGT1A9I399C/C-1818C/T组比较,I399C/T-1818C/T组和I399C/T-1818T/T组患者OAAS达4分的时间较长,此时的效应室浓度较低、BIS升至80的时间较长,且组间比较差异有统计学意义(P<0.05)。
5.高效液相色谱法测定血浆丙泊酚浓度
丙泊酚标准色谱图保留时间分别为11.1min和7.1min,此结果显示丙泊酚和内标完全分离,本研究中的丙泊酚检测浓度范围为0.05~25.6μg·mL-1,丙泊酚检测低限0.01μg·mL-1.所得标准曲线回归方程：Y=0.0185X+0.0089,相关系数：r=0.9989。采用0.1、1.6和25.6μg·ml-1三种浓度检测丙泊酚回收率,其检测结果：101.21%、102.07%和99.98%,RSD均小于5%；日内精密度RSD为3.26%～11.00%及日间精密度为2.55%～8.00%。
6.UGT1A9多态性对乳腺良性肿块患者丙泊酚单次注射药动学参数的影响
应用DAS软件对各组血药浓度-时间数据进行曲线拟合和模型识别,根据拟合结果绘制的药-时曲线,均符合三房室开放模型的特点。UGT1A91399C/C、 C/T、T/T各组患者的主要药动学参数为：T1/2α为(1.31±0.11vs1.28±0.11vs1.45±0.10) min、T1/2β为(29.88±3.00vs19.68±1.28vs21.59±l.18) min、T1/2γ为(209.65±31.45vs156.76±13.15vs215.85±20.36) min、为(111.38±3.71vs110.89±2.64vs108.45±3.28)μg·min-1·ml-1、CL为(0.0152±0.0004vs0.0151±0.0003vs0.0151±0.0005) ml·kg·min-1、Cmax为(8.71±0.62vs8.88±0.64vs8.52±0.83) μg·ml-1,三组间比较药动学参数差异无统计学意义(P>0.05); UGT1A9-1818T/T、 T/C、C/C各组患者的主要药动学参数为：T1/2a为(1.35±0.12vs1.33±0.08vs1.43±0.16) min、T1/2β为(26.71±2.22vs21.84±1.64vs20.00±1.25) min、T1/2γ为
(209.52±26.75vs184.98±16.93vs194.58±28.64)min、AUC0→t为(113.808±3.659vs107.342±2.641vs111.959±3.204)μg·min·ml-1、CL为(0.0146±0.0005vs0.155±0.0003vs0.015±0.0003) ml·kg-1·min-1、Cmax为(8.56±0.75vs8.68±0.71vs0.1046±0.0058) μg·ml-,三组间比较药动学参数差异无统计学意义(P>0.05)；因UGT1A9-1887T/G、G/G组患者例数较少,所以合并为一组,与-1887T/T组比较,两组患者(T/T vs TG/GG)的主要药动学参数为：T1/2α为(1.16±0.22vs1.39±0.34) min、T1/2β为(24.65±8.62vs22.23±5.83) min、T1/2γ为(194.02±48.34vs192.78±71.90) mi、AUC0→t为(0.131±0.022vs0.146±0.021) μg·min·ml-1、CL为(0.0150±0.0012vs0.0151±0.0013)ml·kg-1·min-1、Cmax为(8.87±0.63vs8.66±0.74) μg·ml-,两组间比较药动学参数差异无统计学意义(P>0.05)。本实验结果显示UGT1A9代谢酶的多态性不是丙泊酚镇静效应及药动学个体差异的遗传因素,但表观遗传学及多个单核苷酸多态性位点的相互作用,以及样本量等因素均是影响实验结果的因素,因此后期研究中增大样本量、在体外单细胞实验中研究代谢酶基因多态性对丙泊酚代谢的影响,以排除混杂因素对实验结果的影响,真正探究丙泊酚应用过程中产生个体差异的原因,实现以基因为导向的个体化麻醉。
结论
1.中国汉族良性乳腺肿块切除女性患者UGT1A9I399C>T、-1818T>C、-1887T>G等位基因的变异频率分别为52.3%(157/300)、41%(123/300)、9.3%(28/300)；
2.静脉停止靶控输注丙泊酚后患者意识恢复期的镇静效应存在较大的个体差异,UGT1A9I399C>T、-1818T>C、-1887T>G多态性对此镇静效应无显著影响,这些位点不是影响丙泊酚镇静效应的遗传标记物；
3.高效液相色谱法测定丙泊酚血浆浓度,方法简便准确、重现性好,适用丙泊酚血药浓度的检测；
4.各组患者丙泊酚的药-时曲线均符合三房室模型,单次静脉注射丙泊酚后,UGT1A9I399C>T、-1818T>C、-1887T>G多态性对丙泊酚的药动学无明显影响
Background and Objective
Propofol is a widely used clinical rapid-acting intravenous general anesthetics, it has many advantages:rapid onset, short-acting, rapid recovery, large range of safty, fewer adverse reactions, etc. It quickly become the first choice of clinical anesthesia sedative drugs, so it is used for anesthesia induction, maintenance, and also ICU ward for sedation commonly. But there is a big demand and sedative effects of differences in individual who used it for sedation. Study confirmed that genetic factors can alter metabolism enzyme activity, thus affect the drug pharmacokinetics and pharmacodynamics, resulting in sedative effects of individual differences. Therefore, to observe the association of UGT1A9gene polymorphisms with propofol pharmacodynamics of target-controlled infusion and pharmacokinetics of single injection in benign breast tumor resection patients under general anesthesia and to achieve reasonable safety for clinical anesthetics use and provide a theoretical basis are the purpose of this study.
Materials and Methods
1. Subjects
Total150cases, American Society of Anesthesiologists (ASA) physical status: I or II,20～49years, and body mass index in the normal range (1±20%), undergoing selective benign breast tumor resection were included. Exclusion criteria: history of alcohol abuse, smoking, psychiatric disease, diabetes mellitus, significant cardiovascular diease, hepatic or renal dysfunction, chronic analgesia use, recently used liver drug metabolizing inducers or inhibitors, and patients with long-term use of sedative and hypnotic drugs. Subjects were divided into three groups according to the genotypes:wild-type homozygotes, mutant heterozygous, homozygous mutant. The protocol of this study was approved by the Ethical Committee of the First Affiliated Hospital of Zhengzhou University, and informed consent was obtained from all patients enrolled in this study.
2. Anesthesia
2.1Pharmacodynamic section
All patients using a uniform method of TIVA, administer propofol by target controlled infusion (TCI), induction of anesthesia:plasma concentration of propofol TCI is3μg/ml, intravenous remifentanil and cis-atracurium after the patients lost their consciousness, skilled anesthetists insert Laryngeal mask and mechanical ventilation. Anesthesia was maintained with propofol TCI3μg-ml-1and remifentanil and change the maintenance dose to ensure the patients maintain stable vital signs. We disable the cis-atracurium and remifentanil before the end of surgery30min and5min, stop the propofol TCI at the end of the surgery and intravenous atropine and neostigmine antagonistic muscle relaxants, assessment of the propofol sedation effects at the same time, removal of the laryngeal mask until the patients'conscious and breathing recovery good.
Record time, effect-site concentration and BIS value after stop injecting of propofol to the patient's OAA/S (the Observer's Assessment of Alertness/Sedation Scale) was4, record the time and effect-site concentration when patients recover their consciousness (BIS value back to80).
2.2Pharmacokinetic section
All30subjects use a standardized general anesthesia technique. General anesthesia was induced with propofol2mg/kg, remifentanil1.5μg/kg and cis-atracurium0.15mg/kg within60s, insert Laryngeal mask and mechanical ventilation, main end-tidal partial pressure of carbon dioxide at35～45mmHg. Remifentanyl (0.1-0.2μg/kg/min) and sevoflurane (1%-2%) were used for anesthesia maintenance during the operation. We withdrawal drugs and antagonize muscle relaxants at the end of the surgery.
3. Evaluation of propofol sedation effects
Observe and record the time, BIS value and effect-site concentration after stop propofol target controlled infusion to patients OAA/S was4points, time and effect-site concentration of patient recovery of consciousness, to regard awareness convalescent evaluation as propofol indicators of sedative effect after target-controlled infusion.
4. Genotyping assays
Collect2ml venous blood samples from all patients in this study. DNA was extracted from leukocytes in peripheral blood using DNA extraction kit, genotyping of UGT1A91399C>T-1818T>C and-1887T>G alleles was conducted by polymerase chain reaction (PCR) and direct sequence anaylsis.
5. Collect blood samples
In the first part, blood samples were collected when patients BIS value was back to80after stop propofol target controlled infusion.In the second part,3ml blood samples were taken after propofol injection through ulnar vein at the time of1,3,5,10,15,30,45,60,90,120,240,360min. After3000r/min centrifugal plasma lOmin, shifted the upper to2ml EP tube and stored at-80℃refrigerator. We use high performance liquid chromatography to detect blood concentration of propofol. Propofol plasma concentration was processed using DAS pharmacokinetic software by the Chinese Pharmacological Society prepared by the commission in this study, selecting the best compartment model, drawing blood drug concentration-time curves and obtaining pharmacokinetic parameters.
Statistical analysis
SPSS17.0software was used for statistical analysis(SPSS Inc, Chicago, IL, USA). The Chi-square test was used to verify Hardy-Weinberg equilibrium. Data for numerical variables are expressed as mean±standard deviation (x±s). One-way analysis of variance (ANOVA) was used to assess whether significant differences exist among the three genotypes. Data for the time, effect-site concentration and BIS value were compared using one-way analysis of variance with post hoc Bonferroni correction, multiple comparisons was performed before and after adjusted for age, height, weight of the patients and duration of anesthesia. Propofol standard curve regression equation using linear regression and correlation processing, amount of data used by a single factor analysis of variance. A P<0.05(two-sided) was considered statistically significant.
Results
1. General information
Every three groups according to UGT1A9SNP of patient's age, weight, height, anesthesia time, medication, blood loss, fluid volume, liver's and kidneys function and others have no significant difference in the two parts of this artical (P>0.05).
2. Distribution of UGT1A9allele
The frequency of UGT1A91399C>T,-1818T>C,-1887T>G allele in Han Chinese patients with breast surgery was52.3%,41%,9.3%. The allele frequency was in Hardy-Weinberg equilibrium (P>0.05), which indicates that the patient pool was likely representative of the population being studied. The allelic frequency of UGT1A9I399C>T in our study was similar to that reported in the literature of the Chinese Han (55.0%)(P>0.05), but lower than the Japanese population (64.4%) and higher than the Caucasus people(38%), and the difference have statistically significant(P<0.05).
3. Sedation effects of propofol TCI in patients are quite different
The results showed that there is a big individual different in propofol efficacy. Stopping propofol TCI injection to patients OAA/S was4, the time1-18mina difference of18times, the effect-site concentration1.2～2.9μg-ml-1(2.2±0.4μg-ml-1) a difference of2.5times, BIS values of51～80(69±7) a difference of1.9times; patients with BIS>80time2～29min a difference of15times, the effect-site concentration0.9～2.8μg·ml-1(1.9±0.4μg-ml-1) a difference of3.3times. Indicators of efficacy between the maximum and minimum values show large individual differences.
4. Association of UGT1A9gene polymorphism with propofol TCI sedation effect
According to the genotype of UGT1A9I399C>T,-1818T>C,-1887T>G, patients were divided into three genotypes of homozygous wild group, heterozygous and mutant homozygous group. No statistical differences in general information among every three genotype groups (P>0.05). No statistical differences in propofol sedative effects after stopping propofol TCI to the patients OAA/S was4among the every three genotype groups (P>0.05). After age, weight, height and duration of anesthesia as a covariate analysis of covariance, there were no significant difference in propofol sedative effects too (P>0.05). Propofol sedative effect indicators after stop TCI, compared with UGT1A9I399C/C-1818C/T group, I399C/T-1818C/T group and I399C/T-1818T/T group patients had a long time and low effect-site concentration when OAA/S was4, and had a long time to BIS value back to80, the difference between groups was statistically significant(P<0.05).
5. High performance liquid chromatographic determination of propofol concentration in plasma
Propofol and internal standard retention times were11.1min and7.1min in standard chromatograms, which indicated that they are completely separated. Detection range of propofol concentration is0.04～25μg. ml-1, and0.01～g-ml-1is the minimum detection limits. Propofol three detection rate concentrations of0.1,1and25μg-ml-1were97.17%,103.79%, and98.18%, respectively, and RSD<5%. RSD of day precision was1.72%-2.34%and inter-day precision was2.18%-4.38%.
6. Pharmacokinetic parameters of propofol
Blood propofol concentration-time data curve were identified by DAS soft ware, and in line with the three compartment open model features. Primary ph armacokinetic parameters:UGT1A9I399C/C, C/T, T/T T1/2α(1.31±0.llvsl.28±0.11vs1.45±0.10)min,T1/2p(29.88±3.00vs19.68±1.28vs21.59±1.18)min,T1/2γ(209.65±31.4 5vs56.76±13.15vs215.85±20.36)min,AUC0→t(111.38±3.71vs110.89±2.64vs108.45±3.28)μg·min-1·ml-1,CL(0.0152±0.0004vs0.0151±0.0003vs0.015l±0.0005)ml·kg-1·min-1, Cmax (8.71±0.62vs8.88±0.64vs8.52±0.83) mg/l, there was no statistically signific ant differences among the three groups about pharmacokinetic parameters(P>0.05). UGT1A9-1818T/T, T/C, C/C T1/2α(1.35±0.12vsl.33±0.08vsl.43±0.16)min, T1/2β(26.71±2.22vs21.84±1.64vs20.00±1.25)min, T1/2γ(209.52±26.75vs184.98±16.93vsl94.58±28.64)min, AUC0→t(113.808±3.659vs107.342±2.641vs111.959±3.204)μ g·min-1·ml-1, CL(0.0146±030005vs0.l55±0.0003vs0.015±0.0003)ml·kg-1·min-1,Cmax (8.56±0.75v58.68±0.71vs0.1046±0.0058) mg/1, there was no statistically signific ant differences among the three groups about pharmacokinetic parameters(P>0.05). UGT1A9-1887(T/TvsTG/GG) T1/2α(1.16±0.22vsl.39±0.34)min, T1/2β(24.65±8.62vs22.23±5.83)min, T1/2γ(194.02±48.34vsl92.78±71.90)min, AUC0→t(0.131±0.022vs0.146±0.021)μg·min-1·ml-1, CL(0.0150±0.0012vs0.0151±0.0013)ml·kg-1·min-1,max为(8.87±0.63vs8.66±0.74) mg/1, there was no statistically significant difference s between the two groups (P>0.05).
Our results show that UGT1A9polymorphism was not one of the genetic factors that lead to propofol pharmacodynamics and pharmacokinetics individual differences. Epigenetics, interaction of multiple single nucleotide polymorphisms (SNPs), and sample size are all factors that influence the results. To exclude confounding factors that impact our results, we will increase the sample size and study metabolic enzyme gene polymorphism on the metabolism of propofol in vitro single cell experiments in late study. Explore the reasons for individual differences of propofol, to achieve gene-oriented individualized anesthesia.
Conclusion
1. The frequencies of UGT1A91399OT,-1818T>C,-1887T>G allele in Chinese Han benign breast lumpectomy female patients are52.33%(157/300),41%(123/300),9.33%(28/300) respectively.
2. There are large individual differences of propofol sedative effects in patients with consciousness recovering after stopping target-controlled infusion of propofol, UGT1A91399OT,-1818T>C,-1887T>G polymorphism have no significant effect on this and were not one of genetic markers that can affect propofol sedation effects.
3. Propofol plasma concentration was determined by high performance liquid chromatography, which is a simple, accurate and reproducible method that can be used in clinical blood propofol concentration monitoring and pharmacokinetic studies.
4. Three groups of propofol concentration-time curves meet the three compartment model, UGT1A9gene polymorphisms have no significant effects on the propofol pharmacokinetic characteristics after single intravenous injection.
丙泊酚(propofol)是一临床应用广泛的速效强效静脉麻醉镇静药物,其具有诸多优点：诱导迅速平稳、体内代谢速度快、停药后苏醒快、安全范围较大、不良反应少等,已经成为全球用量最大的成人临床麻醉和ICU镇静的静脉麻醉药。但文献报道其镇静效应及药代动力学存在较大的个体差异,代谢酶等遗传因素的改变可以影响药物的药代动力学及药效动力学,而镇静药物临床镇静效应的个体差异可能就是受其代谢酶基因多态性的影响。本研究的目的是分析尿苷二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyl tansferase, UGTs)基因1A9多态性对良性乳腺肿块切除术女性患者停止靶控输注丙泊酚后,患者意识恢复期丙泊酚镇静效应个体差异的影响,以及对单次静脉注射丙泊酚后药代动力学的影响,为临床麻醉提供合理的用药方案,为实现以基因为导向的个体化用药提供实验依据。
方法
1.研究对象与分组
选择150例于郑州大学第一附属医院择期行良性乳腺肿块切除手术女性患者,ASA分级：I或Ⅱ级,年龄在20-50岁之间,体重指数范围(1±20%)。术前常规检查心、肝、肺、肾功能均无异常,排除标准：有吸烟史、酗酒史、精神病及癫痫病史、糖尿病、甲亢、内分泌功能紊乱、严重心血管系统疾病、肾脏病、肝脏病史、近期使用过肝药酶诱导剂或抑制剂、长期服用镇静催眠药物的患者。根据UGT1A9基因型检测结果将患者分为野生型纯合子、突变型杂合子和突变型纯合子三组。此研究设计方案通过了郑州大学第一附属医院伦理委员会的批准,患者了解本试验过程并均签署知情同意书后纳入该试验。
2.麻醉方法
2.1药效学部分
本试验中纳入的所有患者均采用统一的静脉麻醉方法,丙泊酚应用靶控输注(TCI)给药模式,麻醉诱导：丙泊酚TCI血浆靶控浓度为3μg/ml,待患者意识消失后静脉注射瑞芬太尼和顺式阿曲库铵,置入喉罩并机械通气；麻醉维持：术中所有患者均以丙泊酚血浆靶控浓度3μg/ml,持续静脉输注瑞芬太尼和间断静脉注射顺式阿曲库铵；在手术结束前30min和5min分别停用顺式阿曲库铵和瑞芬太尼,手术结束即刻停止丙泊酚的靶控输注,同时静脉注射阿托品和新斯的明进行肌松药的拮抗,并对患者进行丙泊酚镇静效应的评估,待患者神志清醒并且自主呼吸恢复良好后拔除喉罩。
2.2药动学部分
所有患者采用统一的全凭静脉麻醉方法,麻醉诱导：30例患者于20s内恒速静脉推注丙泊酚2mg-kg-1、瑞芬太尼1.5μg·kg-1、顷阿曲库铵0.15μg·kg-1待患者意识消失并且肌肉松弛良好后,置入喉罩进行机械通气管理,维持患者的呼气末二氧化碳分压在35-45mmHg范围内波动；麻醉维持：持续吸入1%～2%七氟烷,持续输注瑞芬太尼0.2～0.3μg·kg-1,依麻醉深浅随时调整维持麻醉药物剂量以确保所有患者术中生命体征平稳。术毕及时停药和进行肌松药的拮抗。检测患者UGT1A9基因型,分别分为UGT1A91399C/C(野生型纯合子)I399C/T(突变型杂合子)1399T/T(突变型纯合子)；-1818T/T(野生型纯合子)-1818C/T(突变型杂合子)-1818C/C(突变型纯合子)；-1887T/T(野生型纯合子)-1887T/G(突变型杂合子)-1887G/G(突变型纯合子)。
3.丙泊酚镇静效应的评价
评估并记录停止靶控输注丙泊酚至患者警觉-镇静评分(OAA/S)达到4分的时间、效应室浓度和BIS值,患者意识恢复时(BIS>80)的时间和效应室浓度,以此作为评价停止丙泊酚靶控输注后意识恢复期患者镇静效应的指标。
4.基因型检测
术前采集患者静脉血样1ml,于一周内应用DNA提取试剂盒提取患者的基因组DNA,而后采用聚合酶链反应(polymerase chain reaction, PCR)及直接测序技术,对UGT1A9I399C>T、-1818T>C、-1887T>G多态性位点进行检测分析。
5.血标本采集
药效学部分,停止丙泊酚靶控输注后,于患者BIS升至80时经对侧肘静脉抽取血样3ml,药动学部分,于丙泊酚单次静脉注射后采集患者血样,采血时间分别为：1、3、5、10、15、30、45、60、90、120、240和360min经给药对侧肘静脉抽取血样3ml,EDTA抗凝后3000r/min离心10min,抽取上层血浆2ml保存在EP管内,冻存于-80℃冰箱待测,采用高效液相色谱荧光法检测血浆中的丙泊酚浓度。本实验应用由中国药理学会专业委员会编制的DAS药动学软件处理丙泊酚血药浓度-时间数据,选择最佳房室模型,绘制曲线并求得药动学参数。
统计学分析
采用SPSS17.0软件分析本研究的实验数据,以均数士标准差(x±s)表示计量资料,以x2检验检测等位基因和基因型分布是否符合Hardy-Weinberg平衡；x2检验或Fisher's精确概率法检测不同种族间基因多态性的分布差异；采用单因素方差分析(ANOVA)多组间数据,采用LSD法用于各组间比较。为排除混杂因素的影响,代谢酶不同基因型组间丙泊酚镇静效应的比较采用协方差分析。采用x2检验或Fisher's精确概率法比较各组间不良反应发生率。采用直线相关分析来分析计量资料变量之间的关系。采用直线相关与回归进行处理丙泊酚标准曲线回归方程,检验水准a=0.05。
结果
1.一般情况
纳入本实验的各组患者的年龄、BMI、麻醉时间、手术时间、相关麻醉药品的使用量、术中失血量、输液量、肝肾功能等实验室检查结果等指标组间比较差异均无统计学意义(P>0.05)。
2.乳腺良性肿块患者中UGT1A9等位基因频率
在中国汉族乳腺手术患者UGT1A91399C>T、-18181>C、-18871>G等位基因频率分别为52.3%、41%和9.3%,其等位基因和基因型分布符合Hardy-Weinberg平衡(P>0.05)。其中,UGT1A91399C>T等位基因频率与文献报道的中国汉族(55.0%)无差异(P>o.05),但比日本人群(64.4%)低,比高加索人(38%)高,差别均有统计学意义(P<0.05)。UGT1A9-1818T>C、-18871>G等位基因频率与文献报道的中国汉族(47.6%和9.5%)无差异(P>o.05)。
3.乳腺良性肿块患者丙泊酚TCI药效指标存在较大差异.
本研究结果显示,患者意识恢复期丙泊酚的镇静效应存在较大的个体差异,停止靶控输注丙泊酚至患者OAA/S达到4分的时间5(3,7)min相差18倍,效应室浓度102～209μg·ml-1(2.2±0.4μg·ml-1)相差2.5倍,BIS值51～80(69±7)相差1.9倍；患者BIS>80的时间8(6,11)min相差15倍,效应室浓度0.9-2.8μg·ml-1(1.9±0.4μg-ml-1)相差3.3倍。患者意识恢复期丙泊酚的各项镇静效应指标的最大值和最小值之间呈现较大的个体差异。
4.UGT1A9多态性对乳腺良性肿块患者丙泊酚镇静效应的影响
所有患者根据UGT1A9I399C>T、-1818T>C、-1887T>G基因型检测结果分为野生纯合子组、突变杂合子组和突变纯合子组。一般情况比较各组件差异无统计学意义(P>0.05)；各组间患者肝肾功能等实验室检查结果比较差异均无统计学意义(P>0.05)；停止靶控输注丙泊酚后患者意识恢复期各丙泊酚镇静效应指标在UGT1A9I399C>T、-1818T>C、-1887T>G各基因型组间比较差异无统计学意义(p>0.05)；将患者的年龄、BMI和手术时间作为协变量对实验结果进行协方差分析后的结果表明丙泊酚镇静效应各基因组间差异无统计学意义(P>0.05)；停止靶控输注丙泊酚后患者意识恢复期丙泊酚镇静效应指标,与UGT1A9I399C/C-1818C/T组比较,I399C/T-1818C/T组和I399C/T-1818T/T组患者OAAS达4分的时间较长,此时的效应室浓度较低、BIS升至80的时间较长,且组间比较差异有统计学意义(P<0.05)。
5.高效液相色谱法测定血浆丙泊酚浓度
丙泊酚标准色谱图保留时间分别为11.1min和7.1min,此结果显示丙泊酚和内标完全分离,本研究中的丙泊酚检测浓度范围为0.05~25.6μg·mL-1,丙泊酚检测低限0.01μg·mL-1.所得标准曲线回归方程：Y=0.0185X+0.0089,相关系数：r=0.9989。采用0.1、1.6和25.6μg·ml-1三种浓度检测丙泊酚回收率,其检测结果：101.21%、102.07%和99.98%,RSD均小于5%；日内精密度RSD为3.26%～11.00%及日间精密度为2.55%～8.00%。
6.UGT1A9多态性对乳腺良性肿块患者丙泊酚单次注射药动学参数的影响
应用DAS软件对各组血药浓度-时间数据进行曲线拟合和模型识别,根据拟合结果绘制的药-时曲线,均符合三房室开放模型的特点。UGT1A91399C/C、 C/T、T/T各组患者的主要药动学参数为：T1/2α为(1.31±0.11vs1.28±0.11vs1.45±0.10) min、T1/2β为(29.88±3.00vs19.68±1.28vs21.59±l.18) min、T1/2γ为(209.65±31.45vs156.76±13.15vs215.85±20.36) min、为(111.38±3.71vs110.89±2.64vs108.45±3.28)μg·min-1·ml-1、CL为(0.0152±0.0004vs0.0151±0.0003vs0.0151±0.0005) ml·kg·min-1、Cmax为(8.71±0.62vs8.88±0.64vs8.52±0.83) μg·ml-1,三组间比较药动学参数差异无统计学意义(P>0.05); UGT1A9-1818T/T、 T/C、C/C各组患者的主要药动学参数为：T1/2a为(1.35±0.12vs1.33±0.08vs1.43±0.16) min、T1/2β为(26.71±2.22vs21.84±1.64vs20.00±1.25) min、T1/2γ为
(209.52±26.75vs184.98±16.93vs194.58±28.64)min、AUC0→t为(113.808±3.659vs107.342±2.641vs111.959±3.204)μg·min·ml-1、CL为(0.0146±0.0005vs0.155±0.0003vs0.015±0.0003) ml·kg-1·min-1、Cmax为(8.56±0.75vs8.68±0.71vs0.1046±0.0058) μg·ml-,三组间比较药动学参数差异无统计学意义(P>0.05)；因UGT1A9-1887T/G、G/G组患者例数较少,所以合并为一组,与-1887T/T组比较,两组患者(T/T vs TG/GG)的主要药动学参数为：T1/2α为(1.16±0.22vs1.39±0.34) min、T1/2β为(24.65±8.62vs22.23±5.83) min、T1/2γ为(194.02±48.34vs192.78±71.90) mi、AUC0→t为(0.131±0.022vs0.146±0.021) μg·min·ml-1、CL为(0.0150±0.0012vs0.0151±0.0013)ml·kg-1·min-1、Cmax为(8.87±0.63vs8.66±0.74) μg·ml-,两组间比较药动学参数差异无统计学意义(P>0.05)。本实验结果显示UGT1A9代谢酶的多态性不是丙泊酚镇静效应及药动学个体差异的遗传因素,但表观遗传学及多个单核苷酸多态性位点的相互作用,以及样本量等因素均是影响实验结果的因素,因此后期研究中增大样本量、在体外单细胞实验中研究代谢酶基因多态性对丙泊酚代谢的影响,以排除混杂因素对实验结果的影响,真正探究丙泊酚应用过程中产生个体差异的原因,实现以基因为导向的个体化麻醉。
结论
1.中国汉族良性乳腺肿块切除女性患者UGT1A9I399C>T、-1818T>C、-1887T>G等位基因的变异频率分别为52.3%(157/300)、41%(123/300)、9.3%(28/300)；
2.静脉停止靶控输注丙泊酚后患者意识恢复期的镇静效应存在较大的个体差异,UGT1A9I399C>T、-1818T>C、-1887T>G多态性对此镇静效应无显著影响,这些位点不是影响丙泊酚镇静效应的遗传标记物；
3.高效液相色谱法测定丙泊酚血浆浓度,方法简便准确、重现性好,适用丙泊酚血药浓度的检测；
4.各组患者丙泊酚的药-时曲线均符合三房室模型,单次静脉注射丙泊酚后,UGT1A9I399C>T、-1818T>C、-1887T>G多态性对丙泊酚的药动学无明显影响
Background and Objective
Propofol is a widely used clinical rapid-acting intravenous general anesthetics, it has many advantages:rapid onset, short-acting, rapid recovery, large range of safty, fewer adverse reactions, etc. It quickly become the first choice of clinical anesthesia sedative drugs, so it is used for anesthesia induction, maintenance, and also ICU ward for sedation commonly. But there is a big demand and sedative effects of differences in individual who used it for sedation. Study confirmed that genetic factors can alter metabolism enzyme activity, thus affect the drug pharmacokinetics and pharmacodynamics, resulting in sedative effects of individual differences. Therefore, to observe the association of UGT1A9gene polymorphisms with propofol pharmacodynamics of target-controlled infusion and pharmacokinetics of single injection in benign breast tumor resection patients under general anesthesia and to achieve reasonable safety for clinical anesthetics use and provide a theoretical basis are the purpose of this study.
Materials and Methods
1. Subjects
Total150cases, American Society of Anesthesiologists (ASA) physical status: I or II,20～49years, and body mass index in the normal range (1±20%), undergoing selective benign breast tumor resection were included. Exclusion criteria: history of alcohol abuse, smoking, psychiatric disease, diabetes mellitus, significant cardiovascular diease, hepatic or renal dysfunction, chronic analgesia use, recently used liver drug metabolizing inducers or inhibitors, and patients with long-term use of sedative and hypnotic drugs. Subjects were divided into three groups according to the genotypes:wild-type homozygotes, mutant heterozygous, homozygous mutant. The protocol of this study was approved by the Ethical Committee of the First Affiliated Hospital of Zhengzhou University, and informed consent was obtained from all patients enrolled in this study.
2. Anesthesia
2.1Pharmacodynamic section
All patients using a uniform method of TIVA, administer propofol by target controlled infusion (TCI), induction of anesthesia:plasma concentration of propofol TCI is3μg/ml, intravenous remifentanil and cis-atracurium after the patients lost their consciousness, skilled anesthetists insert Laryngeal mask and mechanical ventilation. Anesthesia was maintained with propofol TCI3μg-ml-1and remifentanil and change the maintenance dose to ensure the patients maintain stable vital signs. We disable the cis-atracurium and remifentanil before the end of surgery30min and5min, stop the propofol TCI at the end of the surgery and intravenous atropine and neostigmine antagonistic muscle relaxants, assessment of the propofol sedation effects at the same time, removal of the laryngeal mask until the patients'conscious and breathing recovery good.
Record time, effect-site concentration and BIS value after stop injecting of propofol to the patient's OAA/S (the Observer's Assessment of Alertness/Sedation Scale) was4, record the time and effect-site concentration when patients recover their consciousness (BIS value back to80).
2.2Pharmacokinetic section
All30subjects use a standardized general anesthesia technique. General anesthesia was induced with propofol2mg/kg, remifentanil1.5μg/kg and cis-atracurium0.15mg/kg within60s, insert Laryngeal mask and mechanical ventilation, main end-tidal partial pressure of carbon dioxide at35～45mmHg. Remifentanyl (0.1-0.2μg/kg/min) and sevoflurane (1%-2%) were used for anesthesia maintenance during the operation. We withdrawal drugs and antagonize muscle relaxants at the end of the surgery.
3. Evaluation of propofol sedation effects
Observe and record the time, BIS value and effect-site concentration after stop propofol target controlled infusion to patients OAA/S was4points, time and effect-site concentration of patient recovery of consciousness, to regard awareness convalescent evaluation as propofol indicators of sedative effect after target-controlled infusion.
4. Genotyping assays
Collect2ml venous blood samples from all patients in this study. DNA was extracted from leukocytes in peripheral blood using DNA extraction kit, genotyping of UGT1A91399C>T-1818T>C and-1887T>G alleles was conducted by polymerase chain reaction (PCR) and direct sequence anaylsis.
5. Collect blood samples
In the first part, blood samples were collected when patients BIS value was back to80after stop propofol target controlled infusion.In the second part,3ml blood samples were taken after propofol injection through ulnar vein at the time of1,3,5,10,15,30,45,60,90,120,240,360min. After3000r/min centrifugal plasma lOmin, shifted the upper to2ml EP tube and stored at-80℃refrigerator. We use high performance liquid chromatography to detect blood concentration of propofol. Propofol plasma concentration was processed using DAS pharmacokinetic software by the Chinese Pharmacological Society prepared by the commission in this study, selecting the best compartment model, drawing blood drug concentration-time curves and obtaining pharmacokinetic parameters.
Statistical analysis
SPSS17.0software was used for statistical analysis(SPSS Inc, Chicago, IL, USA). The Chi-square test was used to verify Hardy-Weinberg equilibrium. Data for numerical variables are expressed as mean±standard deviation (x±s). One-way analysis of variance (ANOVA) was used to assess whether significant differences exist among the three genotypes. Data for the time, effect-site concentration and BIS value were compared using one-way analysis of variance with post hoc Bonferroni correction, multiple comparisons was performed before and after adjusted for age, height, weight of the patients and duration of anesthesia. Propofol standard curve regression equation using linear regression and correlation processing, amount of data used by a single factor analysis of variance. A P<0.05(two-sided) was considered statistically significant.
Results
1. General information
Every three groups according to UGT1A9SNP of patient's age, weight, height, anesthesia time, medication, blood loss, fluid volume, liver's and kidneys function and others have no significant difference in the two parts of this artical (P>0.05).
2. Distribution of UGT1A9allele
The frequency of UGT1A91399C>T,-1818T>C,-1887T>G allele in Han Chinese patients with breast surgery was52.3%,41%,9.3%. The allele frequency was in Hardy-Weinberg equilibrium (P>0.05), which indicates that the patient pool was likely representative of the population being studied. The allelic frequency of UGT1A9I399C>T in our study was similar to that reported in the literature of the Chinese Han (55.0%)(P>0.05), but lower than the Japanese population (64.4%) and higher than the Caucasus people(38%), and the difference have statistically significant(P<0.05).
3. Sedation effects of propofol TCI in patients are quite different
The results showed that there is a big individual different in propofol efficacy. Stopping propofol TCI injection to patients OAA/S was4, the time1-18mina difference of18times, the effect-site concentration1.2～2.9μg-ml-1(2.2±0.4μg-ml-1) a difference of2.5times, BIS values of51～80(69±7) a difference of1.9times; patients with BIS>80time2～29min a difference of15times, the effect-site concentration0.9～2.8μg·ml-1(1.9±0.4μg-ml-1) a difference of3.3times. Indicators of efficacy between the maximum and minimum values show large individual differences.
4. Association of UGT1A9gene polymorphism with propofol TCI sedation effect
According to the genotype of UGT1A9I399C>T,-1818T>C,-1887T>G, patients were divided into three genotypes of homozygous wild group, heterozygous and mutant homozygous group. No statistical differences in general information among every three genotype groups (P>0.05). No statistical differences in propofol sedative effects after stopping propofol TCI to the patients OAA/S was4among the every three genotype groups (P>0.05). After age, weight, height and duration of anesthesia as a covariate analysis of covariance, there were no significant difference in propofol sedative effects too (P>0.05). Propofol sedative effect indicators after stop TCI, compared with UGT1A9I399C/C-1818C/T group, I399C/T-1818C/T group and I399C/T-1818T/T group patients had a long time and low effect-site concentration when OAA/S was4, and had a long time to BIS value back to80, the difference between groups was statistically significant(P<0.05).
5. High performance liquid chromatographic determination of propofol concentration in plasma
Propofol and internal standard retention times were11.1min and7.1min in standard chromatograms, which indicated that they are completely separated. Detection range of propofol concentration is0.04～25μg. ml-1, and0.01～g-ml-1is the minimum detection limits. Propofol three detection rate concentrations of0.1,1and25μg-ml-1were97.17%,103.79%, and98.18%, respectively, and RSD<5%. RSD of day precision was1.72%-2.34%and inter-day precision was2.18%-4.38%.
6. Pharmacokinetic parameters of propofol
Blood propofol concentration-time data curve were identified by DAS soft ware, and in line with the three compartment open model features. Primary ph armacokinetic parameters:UGT1A9I399C/C, C/T, T/T T1/2α(1.31±0.llvsl.28±0.11vs1.45±0.10)min,T1/2p(29.88±3.00vs19.68±1.28vs21.59±1.18)min,T1/2γ(209.65±31.4 5vs56.76±13.15vs215.85±20.36)min,AUC0→t(111.38±3.71vs110.89±2.64vs108.45±3.28)μg·min-1·ml-1,CL(0.0152±0.0004vs0.0151±0.0003vs0.015l±0.0005)ml·kg-1·min-1, Cmax (8.71±0.62vs8.88±0.64vs8.52±0.83) mg/l, there was no statistically signific ant differences among the three groups about pharmacokinetic parameters(P>0.05). UGT1A9-1818T/T, T/C, C/C T1/2α(1.35±0.12vsl.33±0.08vsl.43±0.16)min, T1/2β(26.71±2.22vs21.84±1.64vs20.00±1.25)min, T1/2γ(209.52±26.75vs184.98±16.93vsl94.58±28.64)min, AUC0→t(113.808±3.659vs107.342±2.641vs111.959±3.204)μ g·min-1·ml-1, CL(0.0146±030005vs0.l55±0.0003vs0.015±0.0003)ml·kg-1·min-1,Cmax (8.56±0.75v58.68±0.71vs0.1046±0.0058) mg/1, there was no statistically signific ant differences among the three groups about pharmacokinetic parameters(P>0.05). UGT1A9-1887(T/TvsTG/GG) T1/2α(1.16±0.22vsl.39±0.34)min, T1/2β(24.65±8.62vs22.23±5.83)min, T1/2γ(194.02±48.34vsl92.78±71.90)min, AUC0→t(0.131±0.022vs0.146±0.021)μg·min-1·ml-1, CL(0.0150±0.0012vs0.0151±0.0013)ml·kg-1·min-1,max为(8.87±0.63vs8.66±0.74) mg/1, there was no statistically significant difference s between the two groups (P>0.05).
Our results show that UGT1A9polymorphism was not one of the genetic factors that lead to propofol pharmacodynamics and pharmacokinetics individual differences. Epigenetics, interaction of multiple single nucleotide polymorphisms (SNPs), and sample size are all factors that influence the results. To exclude confounding factors that impact our results, we will increase the sample size and study metabolic enzyme gene polymorphism on the metabolism of propofol in vitro single cell experiments in late study. Explore the reasons for individual differences of propofol, to achieve gene-oriented individualized anesthesia.
Conclusion
1. The frequencies of UGT1A91399OT,-1818T>C,-1887T>G allele in Chinese Han benign breast lumpectomy female patients are52.33%(157/300),41%(123/300),9.33%(28/300) respectively.
2. There are large individual differences of propofol sedative effects in patients with consciousness recovering after stopping target-controlled infusion of propofol, UGT1A91399OT,-1818T>C,-1887T>G polymorphism have no significant effect on this and were not one of genetic markers that can affect propofol sedation effects.
3. Propofol plasma concentration was determined by high performance liquid chromatography, which is a simple, accurate and reproducible method that can be used in clinical blood propofol concentration monitoring and pharmacokinetic studies.
4. Three groups of propofol concentration-time curves meet the three compartment model, UGT1A9gene polymorphisms have no significant effects on the propofol pharmacokinetic characteristics after single intravenous injection.
引文
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