伏立康唑在中国健康人体的药代动力学研究

目的建立LC-MS/MS法测定人血浆中伏立康唑的浓度,并用于伏立康唑片剂的人体药代动力学研究。方法 20名中国男性健康志愿受试者单剂量口服伏立康唑片0.2 g后,于服药前及服药后0.25,,0.50,0.75,1.00,1.50,2.00,3.00,4.00,6.00,8.00,12.00,24.00,36.00 h采集静脉血,用LC-MS/MS法测定人血浆中伏立康唑的浓度,并用DAS 2.1.1软件计算主要药代动力学参数。结果受试者口服伏立康唑片后,血浆中伏立康唑的Cmax为(1801.97±641.83)μg·L-1;t1/2为(7.67±1.85)h;tmax为(1.36±0.72)h;AUC0-36 h为(8682.92±4435.53)μg·h.L-1。结论所建立的LC-MS/MS法快速、灵敏、简便,适用于伏立康唑的人体药代动力学研究。     

新疆维吾尔族异基因造血干细胞移植高危患儿的伏立康唑血浆谷浓度的分布特征及对疗效和不良反应的影响

目的:评估伏立康唑血浆谷浓度测定在治疗和预防新疆维吾尔族异基因造血干细胞移植(hematopoietic stem cell,HSCT)高危患儿真菌感染的分布特征,并探讨影响伏立康唑血浆谷浓度的相关因素。方法:采用高效液相色谱法-质谱联用技术测定伏立康唑血浆谷浓度,采用Sanger测序技术检测患儿CYP2C19基因多态性,分析年龄、性别、体质量指数、给药途径、给药剂量和CYP2C19基因多态性对伏立康唑谷浓度的影响。 结果:9例患儿的伏立康唑血浆谷浓度＜0.5 μg·mL^-1,26 例伏立康唑谷浓度＞6 μg·mL^-1。伏立康唑血浆谷浓度与患儿的年龄存在显著相关性(F=2.671,P＜0.05)。静脉途径给药患儿的伏立康唑浓度剂量比结果显著高于口服途径给药的患儿(t=-2.330,P＜0.05)。伏立康唑在超快代谢型患儿中的血浆谷浓度显著低于慢代谢型、中间代谢型和正常代谢型患儿[(1.84±1.47),(4.21±12.26),(2.75±1.91),(3.60±2.13) μg·mL^-1;P＜0.05]。使用伏立康唑后,患儿谷丙转氨酶、谷草转氨酶、总胆红素、血肌酐及尿素氮水平均显著高于使用前水平(P＜0.05)。结论:通过监测伏立康唑血浆谷浓度并联合CYP2C19基因多态性来共同指导异基因HSCT高危患儿使用伏立康唑具有一定的临床意义。     

人血浆中伏立康唑的HPLC测定

目的 建立检测人血浆伏立康唑的高效液相色谱法,并对其在人体内的药代动力学进行研究.方法 以ZORBAX Extend-C18(4.6 mm×250mm,5μm)为色谱柱;乙腈-0.15mol/L磷酸二氢钠-水(45∶20∶35)为流动相,流速0.9ml/min;以劳拉西泮为内标,血浆样品经乙酸乙酯和正己烷(4∶1)混合提取后,在256nm波长下进行检测.结果 伏立康唑在25～1600ng/ml浓度范围内线性关系良好(r=0.9999),定量下限为25ng/ml;50、400和1200ng/ml 3种浓度的日间、日内精密度RSD(n=5)均小于10%;相对回收率均在85%～115%范围内,绝对回收率大于75%.单剂量口服200mg伏立康唑的主要药代动力学参数Tmax、Cmax、t1/2和AUC(0-t)分别为(1.70±0.41)h、(1037.01±81.18)ng/ml、(5.88±0.93)h和(6643.92±696.70)ng·h/ml.健康志愿者单剂口服伏立康唑200mg,其药动学参数与国外相关报道一致.结论 本方法 操作简便,结果 准确;适用于血浆伏立康唑的检测.     

细胞色素P450(CYP)3A5与CYP2C19基因多态性对伏立康唑在健康人体的药代动力学特征的影响

目的研究中国健康人体内细胞色素P450(CYP)3A5、CYP2C19基因多态性对伏立康唑药代动力学的影响。方法用RFLP-PCR法对受试者进行全血CYP3A5、CYP2C19基因分型;建立人血浆中伏立康唑的LC-MS测定方法,检测血药浓度;并对受试者单次口服伏立康唑200 mg后的系列血药浓度进行测定。结果伏立康唑200 mg,CYP2C19突变纯合子的AUC0-36、AUC0-∞值均显著高于野生组;也显著高于突变杂合组;而CL/F值则明显低于野生组。T1/2﹑Cmax等在各组间无统计学差异;伏立康唑各药代动力学参数在CYP3A5各组间均无统计学差异。结论中国人体内CYP2C19基因多态性对伏立康唑的药代动力学过程有显著影响;而CYP3A5基因多态性对伏立康唑的药代动力学过程无明显影响。     

HPLC-MS/MS法同时测定人血浆中伏立康唑及其氮氧化代谢物浓度

目的：建立快速测定人血浆中伏立康唑及其主要代谢物伏立康唑-N-氮氧化物浓度的HPLC-MS/MS方法,用于人体药代动力学研究。方法：以伏立康唑和伏立康唑-N-氮氧化物的D3同位素为内标,血浆样品经蛋白沉淀后,用Agilent ZORBAX SB-Aq色谱柱（2.1 mm × 50 mm,1.8 μm）和API 4000质谱仪进行正离子模式电喷雾离子化分析。流速为0.6 mL·min-1,以甲醇为有机相,0.1%甲酸为水相,按一定程序进行梯度洗脱。结果：伏立康唑和伏立康唑-N-氮氧化物在10.00 ~ 8000 ng·mL-1范围内线性关系良好,该方法的特异性、批内/批间精密度、准确度、介质效应、提取回收率、稳定性和稀释可靠性符合相关要求。结论：建立了一种准确、简便、可靠的HPLC-MS/MS分析方法,成功应用于健康中国人静脉注射4 mg·kg-1伏立康唑后的药代动力学研究。     

伏立康唑人体药代动力学的特征与差异研究

目的:研究健康受试者口服伏立康唑的药代动力学特征和差异.方法:70名健康志愿者单次口服伏立康唑200 mg后,用HPLC-MS/MS方法测定血中的伏立康唑浓度,分析不同个体伏立康唑的体内代谢过程与动力学差异.结果:伏立康唑药代动力学个体差异很大.其代谢特征可分为四种类型,A型占21%,达峰时间最短,而峰浓度最高,分布容积最小,属于快分布型;B型占53%,所有参数均为中间水平;C型占11%,为慢代谢型;D型占14%,峰浓度最低,达峰时间最晚,AUC最低,清除最快,为强代谢型.结论:伏立康唑个体代谢差异很大,需要进行血药浓度监测.     

LC-MS/MS法测定人血浆及唾液中伏立康唑浓度

目的:采用LC-MS/MS法测定人血浆及唾液中伏立康唑的浓度。方法:血浆样品及唾液样品经氢氧化钠碱化,萃取剂萃取后进行分析。使用Agilent C18色谱柱(150 mm×4.6 mm,5μm),以乙腈-0.1%甲酸为流动相,梯度洗脱,流速1.0 mL·min-1。结果:线性范围为10～4 000 ng·mL-1,最低定量限为10 ng·mL-1,萃取回收率为81.3%～94.4%,基质效应为-5.35%～1.25%,日内和日间RSD均<7.9%。结论:所用方法快速、简便、灵敏度高,适用于人血浆伏立康唑浓度测定及药代动力学和生物利用度的研究。     

新疆维吾尔族异基因造血干细胞移植病儿血浆中伏立康唑的浓度测定

目的测定新疆维吾尔族异基因造血干细胞移植( hematopoietic stem cell,HSCT)病儿血浆中伏立康唑浓度。方法采用高效液相色谱法 -质谱联用技术测定接受伏立康唑治疗的 204例异基因 HSCT病儿的伏立康唑谷浓度。结果血浆样品中伏立康唑与 IS的峰面积比在 0.2~20 mg/L浓度范围内呈线性( Y=1.107 2 X?0.051 3,r2 ≥ 0.999 7)。定量下限( LLOQ)、低浓度质控( LQC)、中浓度质控( MQC)和高浓度质控( HQC)的日内、日间精密度的 CV值小于 7.39%,准确度在理论浓度的 ±15%内,提取回收率为 85.46%～95.55%,标准偏差均 <5.0%,室温、短期、长期和冻融冻存稳定性均较好( CV值均小于 10%)。 9例病儿的伏立康唑血浆谷浓度 <0.5 mg/L,26例伏立康唑谷浓度 > 6 mg/L。结论该方法特异性强、灵敏度高、运行时间短,能满足临床伏立康唑血药浓度测定需求。     

炎症对伏立康唑代谢和外周血谷浓度的影响

目的:基于C反应蛋白(CRP)研究不同炎症程度对伏立康唑代谢及外周血谷浓度的影响。方法:回顾性分析2016年1月至12月血液科住院患者使用伏立康唑治疗并同时测定伏立康唑(VCZ)谷浓度、伏立康唑N-氧化(N-oxide VCZ)浓度和C反应蛋白(CRP)浓度,156名患者纳入分析。结果:在3组患者体质量标准化剂量无差异(P=0.477)情况下,重度炎症组(CRP≥100mg·L^-1,n=27)患者VCZ谷浓度(4.60±2.10mg·d^-1)明显高于中度炎症组(40-1,n=37)患者VCZ谷浓度(3.10±1.43mg·L^-1)和轻度炎症组(CRP≤40mg·L^-1,n=92)患者VCZ谷浓度(2.66±1.72mg·L^-1)(P=0.000)。重度炎症组N-oxide VCZ/VCZ(0.38±0.25)明显低于中度(0.64±0.41)和轻度(1.17±1.66)炎症组(P=0.009)。156名患者伏立康唑不良反应发生率为21.8%,而重度炎症组伏立康唑不良反应发生率为44.4%。结论:重度炎症抑制伏立康唑代谢,升高增加稳态谷浓度,增加不良反应发生率,炎症期间需要密切监测伏立康唑血药浓度。     

高效液相色谱法测定人血浆中伏立康唑浓度

目的建立一种快速、灵敏的高效液相色谱法测定人血浆中伏立康唑浓度。方法采用氯仿进行血浆样品萃取,采用高效液相色谱-紫外检测法测定。色谱柱:Diamonsil C18柱(200 mm×4.6 mm,5μm),流动相:0.01 mol.L-1醋酸铵(加冰醋酸、三乙胺各10μL)-乙腈(50∶50),紫外检测波长:255 nm。结果伏立康唑回收率>90%,浓度在0.03~8.80μg.mL-1,伏立康唑和酮康唑的峰面积比与伏立康唑浓度间呈现良好的线性关系(r2=0.999 71),日内和日间RSD均<15%。结论该方法快速、灵敏,适合于伏立康唑的临床血药浓度监测及药动学研究。     

利多卡因血浆与唾液浓度的关系

目的：研究利多卡因唾液浓度（Ｃｓ）与血浆浓度（Ｃｐ）相关性。方法：１０例健康志愿者（男性３人，女性７人）单次ｉｖ盐酸利多卡因（１ｍｇ／ｋｇ）后３０，６０，９０ｍｉｎ分别同时采取唾液及血液标本，用荧光偏振免疫分析法（ＴＤｘ）测定利多卡因浓度。结果：利多卡因唾液浓度与血浆浓度的相关性：（１）３０ｍｉｎ时Ｃｓ与Ｃｐ相关性不显著；（２）６０ｍｉｎ时，Ｃｓ＝０．４０３７＋０．９１９６Ｃｐ，ｒ＝０．６６３２Ｐ＜０．０５，Ｃｓ与Ｃｐ呈正相关；（３）９０ｍｉｎ时，Ｃｓ＝－０．２１６２＋１．５２９９Ｃｐ，ｒ＝０．９０６３，Ｐ＜０．０１Ｃｓ与Ｃｐ呈显著正相关。Ｃｓ／Ｃｐ比值Ｒ＝１．４６７±ｓ０．７０６（ｎ＝３０）。结论：当利多卡因血浆浓度为０．２７ｍｇ／Ｌ～０．９１ｍｇ／Ｌ时，其Ｃｓ与Ｃｐ呈正相关。利多卡因唾液浓度为血浆浓度的１．５倍。     

Saliva secretion of chloroquine in man

The presence of chloroquine in saliva from seven healthy volunteers for 21 days after a single 600 mg oral dose of the drug was established by chromatographic and spectroscopic methods. The results showed the drug to be rapidly absorbed with a tmax in saliva of 3.9 +/- 1.6 h. A long elimination half-life of 7-20 days, calculated from the saliva concentration-time profile, is in agreement with values previously reported for the drug using plasma level data. In three of the volunteers from whom simultaneous blood samples were obtained, the mean Cs/Cp value was 1.20 +/- 0.27. It is suggested that saliva level determination may be used in evaluating patient compliance, therapeutic drug monitoring and pharmacokinetic parameters of chloroquine.     

Effect of antiorthostatic hypokinesia on acetaminophen pharmacokinetics and its distribution in saliva of healthy volunteers

The pharmacokinetics of acetaminophen in a group of healthy volunteers has been studied after a single peroral administration at a dose of 625 mg under normal and antiorthostatic hypokinesia (head-down bed rest) conditions. A highly significant correlation has been established between the concentrations of acetaminophen in the blood plasma and saliva of volunteers and also between the pharmacokinetic parameters calculated from the dynamics of drug distribution in plasma and saliva. Atendency toward increased concentration of acetaminophen in saliva compared to blood plasma of volunteers; decreased time of attaining the maximum drug concentration, relative bioavailability, time of half-elimination, and mean retention time in the organism; and increased general clearance has been observed.     

抽脂患者皮下注射利多卡因血清与唾液浓度的相关性及其药代动力学研究

本文利用高效液相色谱法对12名抽脂健康患者皮下注射利多卡因的血清、唾液及脂肪浓度进行了测定,探讨了血清与唾液中药物浓度的相关性,并比较了二者之间的药代动力学参数。患者的平均给药剂量为20mg/kg,单剂量给药。实验结果表明血清与唾液中药物浓度呈线性关系:r=0.8043(p<0.01),C_(血清)=0.3433C_(唾液)+0.2620(n=78).唾液与血清药物浓度比值为2.37±0.857(比值范围:1.02～4.09,n=78).测得血清及唾液药代动力学参数分别为:吸收速率常数(Ka)0.573±0.583h~(-1),0.478±0.270h~(-1);消除半衰期(t_(1/2)k)6.41±2.08h,5.68±1.76h;达峰时间(T_(max))6.63±1.46h,6.67±1.80h;峰浓度(C_(max))2.52±0.926μg/ml,6.31±2.30μg/ml.血清与唾液的动力学参数除峰浓度(C_(max))外,统计学上均无明显差异(P>0.05).患者被抽出脂肪的药物含量为给药总量的31.84%(20.69～47.90%).     

Pharmacokinetics of diethylcarbamazine: prediction by concentration in saliva

The concentration of diethylcarbamazine in saliva was used to determine pharmacokinetic parameters, in comparison to plasma and urine concentrations. Six healthy adult male volunteers were administered 150 mg diethylcarbamazine with 400 ml of water. At seven different time intervals, blood, urine and saliva samples were taken, and different pharmacokinetic parameters measured. The plasma-saliva concentration ratio was calculated as 1.53 whereas the observed ratio was 3.82. The half lives, times to reach peak plasma concentration, and elimination rate constants did not show any significant difference in the different samples. The plasma peak concentration and areas under the curve were significantly (p<0.05) increased from those of the saliva. At 24 h, when diethylcarbamazine was absent in urine, the plasma and saliva concentrations were almost zero. Diethylcarbamazine is secreted in saliva, and its concentration in saliva can be used to monitor drug therapy.     

Saliva Versus Plasma Bioequivalence of Rusovastatin in Humans: Validation of Class III Drugs of the Salivary Excretion Classification System

Bioequivalence of rusovastatin in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected for 72 h after oral administration of rusovastatin 40 mg to 12 healthy humans. Saliva and plasma pharmacokinetic parameters were calculated by non-compartmental analysis. Analysis of variance, 90 % confidence intervals, and intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated using Kinetica program V5. Human effective intestinal permeability was also calculated by SimCYP program V13. Rusovastatin falls into class III (high permeability/low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A correlation coefficient of 0.99 between saliva and plasma concentrations, and a saliva/plasma concentration ratio of 0.175 were observed. The 90 % confidence limits of area under the curve (AUC_last) and maximum concentration (C_max) showed similar trends in both saliva and plasma. On the other hand, inter- and intra-subject variability values in saliva were higher than in plasma, leading to the need for a slightly higher number of subjects to be used in saliva studies. Non-invasive saliva sampling instead of the invasive plasma sampling method can be used as a surrogate for bioequivalence of SECS class III drugs when an adequate sample size is used.     

Lack of correlation between lithium pharmacokinetic parameters obtained from plasma and saliva

One tablet containing 755 mg of lithium tryptophanate (10.8 mEq of lithium) was administered to eight healthy volunteers. The main pharmacokinetic parameters for the group of subjects were estimated. Pharmacokinetic parameters (mean +/- SD) from plasma and saliva were respectively: half life (t1/2) 17 +/- 6 vs. 21.8 +/- 14 h; mean residence time 23.7 +/- 7.4 vs. 24.4 +/- 15.3 h; total clearance 30.6 +/- 9.3 vs. 28.6 +/- 6.2 ml/h/kg; and apparent volume of distribution 0.71 +/- 0.20 vs. 0.84 +/- 0.37 L/kg. Although the mean pharmacokinetic parameters in plasma and saliva were similar, there was no significant correlation between the calculated parameters in the individual subject (p greater than 0.05). The usefulness of monitoring salivary levels of lithium is questionable.     

Comparison of plasma and saliva concentrations of lamotrigine in healthy volunteers

The relationship between lamotrigine (CAS 84057-84-1) concentrations in saliva and plasma in healthy volunteers were examined, as well as the possibility of using saliva to monitor levels for effective therapy. The study was performed with 14 healthy volunteers, mean age 23 +/- 2 (SD) years. After single oral doses of 200 mg, plasma and stimulated saliva samples were collected simultaneously at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 h. The pH values of saliva samples were recorded. Lamotrigine concentrations were determined by a validated HPLC method. Fraction of drug bound to plasma proteins was calculated mathematically by the modified Henderson-Hasselbalch equation. Linear regression was used to evaluate the correlations. The remnant of orally administered drug contaminated the saliva samples and gave spuriously high values for up to 2 h, which were omitted. There was significant correlation (r2 = 0.677, p < 0.0001) between plasma and saliva concentrations from 2-96 h after administration. The mean ratio of saliva to plasma concentration was 0.426 +/- 0.153 (mean +/- SD). Protein binding, calculated from the concentrations in saliva was 57.5 +/-15.1% (mean +/- SD). Noncompartmental analysis was conducted with the program Kinetica. Plasma t1/2 and MRT were not significantly different from those found from saliva. The mean values of lamotrigine peak saliva concentrations (C(max)), areas under the curve of concentration versus time from zero to infinity (AUC(0-->infinity)), and areas under the curves of the product of time and concentration versus time from zero to infinity (AUMC(0-->infinity) were proportionally lower than in plasma. The results support the use of saliva concentration as a convenient, painless and noninvasive alternative to plasma for monitoring lamotrigine therapy.     

伏立康唑片在中国健康男性体内的生物等效性研究

目的：研究伏立康唑在中国健康男性体内的药代动力学,并评价其相同剂量制剂的生物等效性。方法：19名健康男性志愿者分别单剂量交叉口服伏立康唑片受试制剂或参比制剂200mg,于服药前0h和服药后0．25、0．5、0．75、1、1．5、2、3、4、6、8、12、24、36h抽取4．0mL静脉血,采用高效液相色谱法测定血浆中伏立康唑的浓度。通过DASVer3．0软件计算主要的药动学参数,评价两种制剂的生物等效性。结果：伏立康唑片受试制剂与参比制剂的药动学参数分别为：AUC。（5304．967±3072．252）、（5130．968±2985．462）ng·mL^-1·h;AUC0-∞（5683．143±3438．261）、（5445．115±3181．161）ng·mL^-1·h;Cmax（925．728±356．11）、（1040．251±448：929）ng·mL^-1;tmax（1．566±0．975）、（1．382±0．959）h;t1/2（6.316±2．938）、（5．966±2．276）h。以AUC0-36计算,受试制剂对参比制剂的相对生物利用度为（100．5±3．4）％。结论：两种伏立康唑片在中国健康男性志愿者体内具有生物等效性。     

Kinetics of 4-fluoroquinolones permeation into saliva.

Following a single oral administration of ciprofloxacin, norfloxacin, pefloxacin and ofloxacin preparations to healthy volunteers simultaneously collected, saliva and plasma 4-fluoroquinolone concentrations were assayed by HPLC. Pharmacokinetic properties were determined by ordinary least squares fitting of the two compartment pharmacokinetic model to the experimental data. A good correlation between plasma and saliva data has been demonstrated. The saliva to venous plasma drug concentration ratio S/P appeared to be time-dependent in the case of norfloxacin and pefloxacin. It was demonstrated that S/P is a function of the quotient of the rate of absorption and venous plasma drug concentration. The calculated S/P ratios with the influence of absorption eliminated, (S/P)(corr) are: ciprofloxacin 0.53+/-0.02, norfloxacin 0.34+/-0.04, ofloxacin 0. 43+/-0.02 and pefloxacin 0.39+/-0.02 (mean+/-S.E.). These values are apparently independent of log D thus making it impossible to predict S/P on the basis of partition principles. The corresponding (S/P)(dif) ratios were calculated on the basis of the assumption that an equilibrium is established across the blood-saliva barrier, which is permeable only for nonionized and nonprotein bound drug fraction. Comparing (S/P)(corr) with the calculated (S/P)(dif) ratios it is evident that 4-fluoroquinolone permeation in saliva cannot be described by passive diffusion based on pH-partition theory.