CYP2D6*10基因型对中国室性心律失常病人普罗帕酮药效学的影响(英文)

目的:观察CYP2D6＊10基因型对普罗帕酮在室性心律失常病人中药效学的影响.方法:选择17名室性早搏(VPC≥1000/d)病人.受试者常规实验室检查结果正常,每日3次、每次口服普罗帕酮片剂150-200 mg.于给药前与给药后7 d测定病人心电图和24 h动态心电图(Holter).普罗帕酮稳态峰、谷浓度采用高效液相色谱分析法测定.采用聚合酶链反应(PCR)和限制性片断长度多态性(RFLP)测定CYP2D6＊10基因型.结果:17例室性心律失常病人应用普罗帕酮后,室性早搏总抑制率为79.9％,PR间期延长从0.146 s±0.018 s增加到0.161 s±0.022 s(P<0.05).CYP2D6基因型在普罗帕酮血浆浓度和效应中起着重要作用.450 mg/d剂量组中具有CYP2D6*10 突变纯合子的病人,普罗帕酮血浆峰浓度约为野生基因型的二倍,而且VPC抑制率也增加一倍(P<0.05).结论:CYP2D6＊10基因型与中国心律失常病人CYP2D6酶活性下降有关.普罗帕酮血浆峰浓度增加与室性早搏病人疗效改善相一致.     

国产盐酸西替利嗪片的药代动力学研究

目的 :建立测定国产盐酸西替利嗪 (西可韦 )血药浓度的方法并进行人体药代动力学研究。方法 :采用反相高效液相色谱法 ,以盐酸普罗帕酮为内标 ;色谱柱 :WaterssymmetryC18 不锈钢柱 (3 9mm×150mm ,5μm) ;流动相 :乙腈 -0 02mol/L磷酸二氢钠 -三乙胺 (50∶50∶0 16 ,V/V) ,含十二烷基硫酸钠 (SDS)4 0mmol/L ;流速 :1 0ml/min ;检测波长 :229nm。测定11名健康男性志愿者单剂量口服西可韦片10mg 的血浆中药物浓度。结果 :线性范围为12 5～800ng/ml,最低检测限为5ng/ml,提取回收率>75 %。11名志愿者的血药浓度数据经3p87软件拟合 ,符合血管外给药二室模型 ,其主要药代动力学参数为 :Cmax=(429 00±108 80)ng/ml,Tmax= (0 91±0 40)h ,K10= (0 18±0 04)/h ,以梯形法计算的AUC0～36= (3312 72±682 39)ng/(ml·h)。结论 :本方法结果准确 ,灵敏度高 ,能满足人体药代动力学研究的需要 ;西可韦主要药代动力学参数与国内、外文献报道一致 ,可广泛应用于临床     

人血浆中吡格列酮的固相萃取高效液相色谱法测定

以吡格列酮的同系物 PIOGA为内标 ,采用 C2 固相萃取紫外检测的 HPL C分析法测定人血浆中吡格列酮的浓度。 C1 8分析柱 (15 0× 4.6 mm,5 μm) ,流动相 :水 -乙腈 -冰醋酸 (5 40∶ 46 0∶ 1.2 ,用氨试液调至 p H6 .0 ) ,流速 :1.0 ml/ min,检测波长 2 6 9nm。取血样 0 .5 m l,加入内标经 C2 固相萃取后进样 40μl。最低定量限 (L OQ)为10 ng/ ml,线性范围为 10～ 16 0 0 ng/ ml     

HPLC-紫外法测定人血浆中芬太尼浓度

目的 :建立高效液相色谱法 -紫外检测器测定人血浆中芬太尼浓度的方法。方法 :本实验采用外标法 ,以Shim -PackCLC -ODS(6 0mm×150mm ,5μm )为固定相 ,含0 015mol/LNaH2PO4 的乙腈 -水溶液 (30∶70 ,v/v)为流动相 ,流速1 5ml/min ,紫外检测波长195nm。结果 :标准曲线在2 0～100ng/ml范围内线性关系良好 (r=0 999) ,最低检测浓度为1ng/ml,方法回收率为(91 70±4 70) % ,提取回收率为 (97 38±3 69) % ,日内变异RSD (6 50±2 79) % ,日间变异RSD (6 70±3 04) %。结论 :本方法简便 ,准确 ,检测浓度低 ,能够满足血浆中低浓度芬太尼的测定及临床药代动力学研究的要求。     

用HPLC柱切换法血浆直接进样测定法莫替丁

本文采用HPLC柱切换技术,建立了以YWG-C18(3cm)为预处理柱,乙酸(0.2mol/L)为预处理流动相,血浆直接进样。在线(on-line)固相净化血浆样品;以Shimpack CLC-ODS(15 cm)为分析柱,甲醇-0.2 mol/L乙酸铵缓冲液(14:86)为流动相,267 nm波长检测,采用外标法定量。测定H₂-受体拮抗剂法莫替丁人体血药浓度的方法。该法净化过程简便,为自动净化血浆样品提供了一选择方法。回收率好(81.10～84.75%);法莫替丁的检测限约为2.4 ng,血浆中最低检出浓度约为12 ng/ml。日内变异系数为4.1%,日间变异系数为4.9%;在浓度为15～210 ng/ml血浆范围内呈线性关系。     

HPLC法快速测定人血浆中酒石酸美托洛尔的浓度

目的:建立快速测定人血浆中酒石酸美托洛尔浓度的方法。方法:血浆样品以3-叔丁基甲醚处理后,采用高效液相色谱法进样测定,色谱柱为Kromasil LC-18DB,流动相为乙腈-10 mmol/L辛烷磺酸钠溶液(p H=2.0)(30∶70),柱温为25℃,流速为1.3ml/min,荧光检测波长为267 nm(激发波长)、290 nm(发射波长),内标为吲哚洛尔。结果:酒石酸美托洛尔血药浓度在2~300 ng/ml范围内线性关系良好(r=0.999 9),最低检测浓度为1 ng/ml。平均方法回收率为(101.13±4.0)%,日内RSD≤2.47%,日间RSD≤4.51%。结论:该方法简便、快速、灵敏、重现性好,适用于酒石酸美托洛尔临床血药浓度监测及人体药动学研究。     

RP-HPLC色谱法测定血浆中地西泮浓度

目的本文建立了血浆中地西泮浓度的HPLC快速测定方法。方法采用氯硝西泮为内标，流动相为甲醇-水（70:3O)，检测波长为254nm。结果地西泮浓度在0．05-15ug／ml范围内线性良好，最低检测浓度为10ng/ml回收率为98．2%-101．5％日内变异系数为0．9％-2．1%日间变异系数为1.3％-2．8％。结论该方法操作简便、快速、准确，灵敏度高，重现性好，适用于临床地西泮血药浓度的快速测定。     

人血浆中西酞普兰的HPLC-荧光法测定

建立了HPLC-荧光法测定人血浆中西酞普兰的浓度.血浆样品经液-液萃取后测定,用Zorbax SB C8色谱柱,磷酸二氢铵缓冲液(pH 3.5)-乙腈(65:35)为流动相,激发波长240 nm,发射波长302 nm.血浆中西酞普兰线性范围为1～100ng/ml,最低定量浓度为1ng/ml,日内、日间RSD均小于4.0%,方法平均回收率为93.2%.     

高效液相色谱法测定血浆中酮基布洛芬的含量

建立测定血浆中酮基布洛芬简便、灵敏的HPLC法.色谱柱为SpherisorbC18柱(10cm×4.6mm,3μ),流动相为5mmol/L磷酸盐缓冲液(pH6.8)-甲醇(28∶72,V/V),流速1ml/min,在UV262nm波长处检测,检测器灵敏度设为0.005aufs,响应时间0.2s.采用内标法定量,内标物为萘普生.1ml血浆样品盐酸酸化后加入6ml乙醚提取,提取液空气吹干,用250μl流动相重溶解后进行分析.实验结果表明,在此分析条件下酮基布洛芬和内标分离完全且无其它干扰,保留时间分别为12.3和9.5min.在0.01～5.0μg/ml浓度范围内酮基布洛芬峰面积比与其浓度间呈良好的线性关系,r=0.9999,血浆中酮基布洛芬最低检测浓度为3ng/ml,回收率85.9%～90.9%,天内变异1.4%～4.9%,天间变异2.5%～6.2%.     

样品固相净化及反相高效液相色谱法测定血浆中茶碱

本文用氧化铝固相净化血样以消除血中杂质及某些合并用药的干扰,用Zorbax-C18柱及甲醇-(0.05 mol/L)醋酸钠缓冲液(50:50)为流动相,254 nm波长检测,咖啡因为内标测定了茶碱人体血浆浓度的变化。该法样品处理简便、快速,净化回收率好(80～86%)茶碱的检测限为0.2ng(信噪比3),在血浆中的最低检测浓度为20 ng/ml。标准曲线r为0.9995,日内变异系数1.89%,日间变异系数为2.41%,方法平均回收率为98.44±0.89%。     

Simultaneous determination of propafenone and 5-hydroxypropafenone in plasma by means of high pressure liquid chromatography

A high pressure liquid chromatographic (HPLC) method with internal analogue standardization for the simultaneous determination of propafenone and 5-hydroxypropafenone in plasma is described. The method comprises extraction from plasma at pH 9 with toluene/dichloromethane/isopropanol, derivatization with dansylhydrazine and subsequent elimination of fluorescent byproducts via silica gel disposable columns followed by quantification by means of fluorescence detection after HPLC separation using a normal phase. With a sample volume of 1 ml the lower limit of detection for propafenone and 5-hydroxypropafenone is approximately 0.2 ng/ml, the limit of determination (precision limit 10%) is approximately 1 ng/ml. The variation coefficients decrease from approximately 10% in the low range to 6-9% for propafenone and 3-7% for 5-hydroxypropafenone at 2 ng/ml and above. For both substances a mean weighted relative error of 6% has to be expected.     

柱前衍生化反相HPLC法测定血浆中普罗帕酮的对映异构体

建立了选择性测定血浆中普罗帕酮对映异构体的柱前衍生化反相HPLC法。用S(+)-1-(1-萘基)乙基异氰酸酯为衍生化试剂,与血浆中提取出的普罗帕酮反应生成非对映立体异构体,以HPLC-UV检测法(220nm)定量。采用此法成功地测试了10名健康受试者单剂量口服300mg盐酸普罗帕酮片后对映异构体的药代动力学曲线。此法灵敏度高(7.5ng·ml^-1),操作简便,重现性好。     

Pharmacokinetic and pharmacodynamic interactions of propafenone and cimetidine

The pharmacokinetics and pharmacodynamics of the extensively metabolized antiarrhythmic agent propafenone were assessed alone and during concomitant administration of cimetidine. Twelve healthy subjects were given successively the following treatments: propafenone 225 mg q8h plus cimetidine placebo; cimetidine 400 mg q8h plus propafenone placebo; and propafenone 225 mg plus cimetidine 400 mg q8h. After a minimum of 5 days on each regimen, plasma drug concentrations and electrocardiogram conduction intervals were measured during a drug washout period. The maximum concentration of propafenone in plasma was 993 +/- 532 ng/mL when propafenone was given alone compared with 1230 +/- 591 ng/mL when propafenone was given with cimetidine (P = .0622). Differences in tmax, t1/2, and Cp ss did not approach statistical significance when propafenone alone was compared with propafenone plus cimetidine. When compared with cimetidine, propafenone significantly increased the PR interval from 161 +/- 5 msec to 192 +/- 6 msec (P less than .01) and the QRS duration from 89 +/- 3 msec to 98 +/- 4 msec (P less than .01). Combination therapy caused a modest additional increase in QRS duration to 103 +/- 3 msec (P less than .01). In conclusion, cimetidine caused small changes in propafenone pharmacokinetics and pharmacodynamics; but these changes are unlikely to be clinically important.     

Bioavailability of an extemporaneous suspension of propafenone made from tablets

Propafenone is an effective antiarrhythmic agent used in children, while in Mexico no specific formulation for children is available, which causes errors in adequate dosage. The aim of this study was to determine the bioavailability of a suspension prepared extemporaneously using commercial tablets of propafenone. The bioavailability was determined in two groups of rabbits (n = 8): the first group received a single intravenous dose of 2 mg/kg of propafenone; the second was orally administered an extemporaneous suspension of propafenone prepared from commercial tablets. Blood samples were drawn at several times during the next 24 h and analysed by HPLC to determine drug levels. The extemporaneous suspension was tested previously with satisfactory results regarding physicochemical and microbiologic stability. The area under the curve (AUC) for the i.v. route was 5600.6 ng/ml.h and for oral administration the AUC was 3327.6 ng/ml.h. The bioavailability was calculated at 59.41%. These results are consistent with previous reports for solid dosage forms. The propafenone suspension prepared extemporaneously using commercial tablets is bioavailable using an animal model; nevertheless, it is necessary to carry out human studies either in volunteers or in patients to confirm these results.     

HPLC determination of 5-hydroxypropafenone in plasma with electrochemical detection

A high pressure liquid chromatographic (HPLC) method with internal analogue standardization for the determination of 5-hydroxypropafenone in plasma is described. The method comprises extraction from plasma at pH 9 with diethyl-ether and quantification after HPLC separation using a reverse phase by means of electrochemical (reductive) detection after electrochemical preoxidation. When using 1 ml plasma the lower limit of detection is 0.5 ng/ml. Under routine conditions the limit of determination is estimated to be lower than 2 ng/ml. The variation coefficients of duplicates drop from about 10% in the range of the determination limit to about 3% at 5 ng/ml and above. The determination of 5-hydroxypropafenone is not impaired by other known metabolites of propafenone.     

High-performance liquid chromatographic method for the simultaneous determination of propafenone and 5-hydroxypropafenone in human serum.

A simple, rapid and sensitive high-performance liquid chromatographic method for the simultaneous determination of propafenone and 5-hydroxypropafenone in human serum is described. Method involves a single-step extraction of the drug and its metabolite with dichloromethane:2-propanol (4:1 v/v) mixture from 0.2 ml of serum. Separation of the investigated compounds on deactivated Supelcosil LC18-DB column is accomplished by ultraviolet detection at 210 nm. The limit of detection is 10 ng/ml for propafenone and 4 ng/ml for 5-hydroxypropafenone. The method is useful for the routine monitoring of propafenone and its main metabolite in serum as well as for the pharmacokinetic studies.     

Tissue distribution of propafenone in the rat after intravenous administration

Tissue distribution of propafenone has been studied in the rat. Measurement of propafenone was made in several tissues: plasma, heart, kidney, lung, liver, muscle, fat and brain, after i.v. administration of 2 mg/kg of the drug. The plasma propafenone kinetics profile can be described by a two-compartmental model. The pharmacokinetic parameters, derived from plasma levels, showed a t1/2 beta of 55.4 min, the central Vd/kg of 2.4 ml/kg, the Cl of 62.8 ml/min.kg and the AUC0-oo of 31.6 micrograms.min/ml. The analysis of the propafenone tissue distribution showed the highest concentration of drug in the lung, followed by the heart and kidneys. A significant concentration was found in brain, muscle and adipose tissue, with concentration ratios (tissue/plasma) above 1. The half-life values obtained for individual organs and tissues are similar to those obtained in plasma, around 1 h. In the post-distributive phase, plasma and tissue concentrations decline in parallel.     

HPLC－紫外法测定人血浆中芬太尼浓度

目的建立高效液相色谱法－紫外检测器测定人血浆中芬太尼浓度的方法。方法本实验采用外标法,以Shim－PackCLC－ODS（60mm×150mm,5μm）为固定相,含0015mol/LNaH2PO4的乙腈－水溶液（30∶70,v/v）为流动相,流速15ml/min,紫外检测波长195nm。结果标准曲线在20～100ng/ml范围内线性关系良好（r=0999）,最低检测浓度为1ng/ml,方法回收率为（9170±470）％,提取回收率为（9738±369）％,日内变异RSD（650±279）％,日间变异RSD（670±304）％。结论本方法简便,准确,检测浓度低,能够满足血浆中低浓度芬太尼的测定及临床药代动力学研究的要求。     

Serum digoxin levels related to plasma propafenone levels during concomitant treatment

Nine patients with supraventricular rhythm disorders were treated during 5-day periods with different oral doses (300, 450, 600, and 900 mg daily) of propafenone concomitantly to long-term digoxin treatment. A poor correlation (r = .398; P less than .05) was obtained when the difference between the mean digoxin serum level (calculated with the Cmin data determined each of the 5 days) observed during a given propafenone dose and the mean digoxin serum level observed before propafenone treatment, was correlated with the dose of propafenone; but an evident correlation (r = .778; P less than .01) was found when the difference in digoxin level was correlated with the plasma propafenone concentration. The propafenone effect of increasing digoxin blood levels was thus concluded to be poorly dose dependent but strongly concentration dependent. The association of propafenone to a long-term digoxin treatment can be considered with a low risk of toxicity when plasma propafenone concentration does not exceed about 1000 ng/mL. Propafenone plasma levels are unpredictable in view of their wide interindividual variation for a given dose, so their measurement is advised to detect high levels and consequently to prevent a rise in digoxin serum concentrations with the possibility of toxicity. In clinical practice, when propafenone concentration determinations are not readily available, digoxin serum levels at least have to be carefully monitored.     

Interaction between digoxin and propafenone

The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. Propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously, the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity.