MTX药代动力学以及组织与全血浓度相关性研究

目的 研究MTX药代动力学以及组织与全血药物浓度相关性。方法 用30mg／m^2 MTX的给药剂量，在肿瘤病人体内研究其药代动力学过程，并对肿瘤局部血及外周血中的药物浓度进行了相关性比较，同时对该剂量下的药品不良反应作了观察。结果 用同30mg／m^2剂量MTX静脉滴注后，肿瘤病人体内药代动力学为一级动力学三房室模型。肿瘤局部与外周血药浓度有显相关性。应用本剂量药品不良反应发生率较低。结论 治疗药物浓度监测可为临床治疗提供客观有效的数据，有指导意义，使用30mg／m^2剂量为一安全有效的治疗剂量。     

甘氨双唑钠(CMNa)对肿瘤病人单剂量和多剂量药代动力学的比较

目的　研究甘氨双唑钠(CMNa)的单剂量和多剂量药代动力学,以对CMNa的蓄积性作一评价。方法　5名肿瘤病人, 连续9次, 静脉滴注剂量为700 mg/m²的CMNa静滴液,用HPLC-二极管阵列紫外法测定受试病人全血CMNa浓度, 并用开放型二室模型拟合CMNa的血药浓度-时间曲线。结果　CMNa在病人体内分布及消除都很快, 单剂量和多剂量静滴CMNa后血药浓度值和各药代动力学参数值非常相近,没有明显差别。结论　甘氨双唑钠在肿瘤病人体内不蓄积,是一个较安全的放疗增敏药物。     

甲氨蝶呤血药浓度动态监测在骨肉瘤治疗中的应用

目的 采用荧光偏振免疫分析(FPIA)法监测大剂量甲氨蝶呤(MTX)化疗的骨肉瘤患者血清中MTX浓度,确定大剂量MTX对骨肉瘤患者进行辅助化疗的个体化用药方案.方法 对15例肝、肾功能正常的骨肉瘤患者采用大剂量MTX 14g/m2配合顺铂及异环磷酰胺(AP-HD-MTX-IFO)的综合治疗方案,于给药后不同时间取血,采用FPIA法测定血清MTX浓度,应用DAS 2.1.1软件计算药代动力学参数,结合患者生化指标及临床表现,调整亚叶酸钙(CF)的解救时间和剂量.结果 确定了每个患者的最佳治疗方案,15例患者均未出现严重不良反应.结论 应用FPIA法可以准确、快速地动态监测MTX血药浓度,得出大剂量MTX在每个骨肉瘤患者体内的药代动力学数据,使骨肉瘤患者的治疗更加安全、有效.     

甘氨双唑钠(CMNa)对肿瘤病人单剂量和多剂量药代动力学的比较

目的:探讨甘氨双唑钠(CMNa)对肿瘤病人单剂量和多剂量药代动力学的比较.方法:选取2016年1月~2017年1月我院收治的肿瘤患者6例,连续静脉滴注剂量为700mg/m2的CMNa9次,通过HPLC-二极管阵列紫外法测定受试患者全血CMNa浓度.结果:CMNa可快速在体内分布并消除,单剂量与多剂量注射无明显的药代动力学差值.结论:CMNa不会在肿瘤患者体内发生聚积,属安全性较高的放疗增敏药物.     

甘氨双唑钠的Ⅰ期临床药代动力学(英文)

目的　对一类新药肿瘤放射增敏剂甘氨双唑钠 (CMNa)进行单剂量和多剂量Ⅰ期临床药代动力学研究 ,对其吸收、分布、代谢、排泄及CMNa在体内的蓄积性作一评价。方法　 6个单剂量组有 2 4名肿瘤病人 ,5名肿瘤病人受试者参与多剂量研究 ;采用高效液相 二极管阵列色谱法测定肿瘤放疗增敏剂CMNa及其代谢产物甲硝唑的血药浓度和尿药浓度 ,用 3P97软件对各单剂量组和多剂量组的血药浓度 时间曲线拟合 ,并计算药代动力学参数。结果6个单剂量组和多剂量组的CMNa血药浓度 时间曲线经拟合均符合开放型二室模型 ,4 0 0 ,5 0 0 ,6 0 0 ,70 0 ,80 0和 90 0mg·m- 2 组的主要药代动力学参数t1/ 2 β为 0 .76～ 2 .6 2h ,cmax为 13.31～ 4 3.90mg·L- 1,AUC为 8.6 8～ 2 9.94mg·h·L- 1,且单剂量组的cmax及AUC与剂量成正比。 70 0mg·m- 2 单次给药和连续 9次给药的多剂量组的肿瘤病人血药浓度 时间曲线几乎相吻合 ,各药代动力学参数值和排泄率没有统计学差异。结论　CMNa在肿瘤病人体内分布和消除均很快 ,一定间隔服用不会在病人体内蓄积 ,是一个较安全的放射增敏药物。     

甲氨蝶呤在儿童的临床药代动力学

本文综述儿童灌流高剂量和口服甲氨蝶呤(MTX)的临床药代动力学。儿童肿瘤患者灌流MTX 后48h 的血浆MTX 浓度不受药物剂量影响;但灌流后6h,灌流结束时血浆MTX浓度与剂量有关。高剂量MTX 的血浆清除呈双相或三相。儿童的α相T_(1/2)为2.45±0.33h,β相T_(1/2)为8.45±3.39h;均龄为8岁的儿童γ相T_(1/2)为35.67±33.62h。MTX 的代谢产物7-羟基-MTX 的血浆浓度与MTX 呈     

健康人伏立康唑血浆浓度与唾液浓度的相关性

目的研究健康人伏立康唑(抗真菌药)血浆和唾液浓度的相关性。方法20名男性健康志愿者分别单剂量口服伏立康唑片200 mg,用液相色谱-串联质谱法测定伏立康唑血浆和唾液浓度,用DAS 2.0软件计算药代动力学参数,用SPSS 10.0比较2种浓度及药代动力学参数的相关性。结果伏立康唑血浆浓度(Cp)和唾液浓度(Cs)的相关性公式Cs=0.69Cp-35.96,γ=0.9710,血浆浓度和唾液浓度呈显著的正向相关关系(P<0.01),Cs/Cp为0.59±0.53。Cs和Cp的药代动力学参数t1/2Ka、t1/2、Tmax较为接近,无显著性差异(P>0.05)。结论可用唾液浓度代替血浆浓度进行伏立康唑的药物浓度监测和人体药代动力学研究。     

氮烯菲林在肿瘤患者的药代动力学

目的研究氮烯菲林(抗肿瘤药)的I期临床药代动力学。方法11名肿瘤病人,随机分成4组,分别静滴氮烯菲林100,150,200,250mg·m-2,用高效液相色谱-紫外法测定受试病人全血中的氮烯菲林及代谢产物(EDMTP-II)的浓度,并计算其药代动力学参数。结果氮烯菲林的血药浓度-时间曲线符合线性开放型二室模型,4个剂量组的t1/2ke为0.10~0.45h内,Cmax在0.77~3.24mg·L-1内,AUC在0.37~1.86mg·h·L-1内。结论氮烯菲林在病人体内分布及消除均较快,且在100~250mg·m-2内,Cmax及AUC与剂量成正比。     

肿瘤患者体内甘氨双唑钠及代谢产物甲硝唑单剂量和多剂量药代动力学及排泄率比较

目的　研究甘氨双唑钠 (CMNa)的单剂量和多剂量药代动力学 ,以评价CMNa的蓄积性。方法　 5名肿瘤病人 ,单次或每隔 1d连续 9次静脉滴注 70 0mg·m- 2 的CMNa液 ,分别在单次和第 9次静滴后设定时间点采血 ,用高效液相色谱 二极管阵列紫外法测定受试病人全血CMNa及其代谢产物甲硝唑浓度 ,对CMNa的血药浓度 时间数据进行了拟合 ,并对单剂量和多剂量的血药浓度 时间数据和药代动力学参数以及尿排泄率进行比较。结果　CMNa在病人体内分布及消除都很快 ,单剂量和多剂量静滴CMNa后血药浓度值和各药代动力学参数非常相近 ,没有明显差别。结论　甘氨双唑钠不会在肿瘤病人体内蓄积。     

高剂量阿米卡星在PICU败血症患儿体内药代动力学的初步研究

目的初步探讨5 mg/kg阿米卡星在PICU患儿体内的药代动力学和血液动力学的关系。方法纳入符合条件的30例革兰阴性败血症患儿进行阿米卡星药物治疗研究,通过非房室模型计算每例患儿的阿米卡星的药代动力学。结果阿米卡星在革兰阴性败血症患儿体内平均药物分布为(0.36±0.07)L/kg,平均血液清除率为(3.88±0.97)m L/(min·kg)。肌酐清除率(CCR)与血清肌酸酐(SCr)相关性差异有统计学意义。结论对PICU患儿应用高剂量阿米卡星(≥25 mg/kg)需要考虑败血症对血液动力学的影响,要密切监测败血症患儿血药浓度变化。     

小剂量甲氨蝶呤治疗银屑病的药动学

目的:研究小剂量甲氨蝶呤(MTX)用于治疗银屑病时的药动学特点并计算其参数.方法:9例银屑病患者单次静脉滴注MTX 12.5 mg,静脉滴注时间为60～90 min.于给药后0,0.2,0.5,1,1.5,2.5,4,6,8,10,12,24 h抽取静脉血,采用荧光偏振免疫分析法测定MTX浓度,用3P87软件计算其药动学参数.结果:小剂量单次静脉滴注MTX符合开放性二室动力学模型.结论:本结果可以为临床用药提供参考依据.     

Pharmacokinetics and toxicity of frequent intermediate dose methotrexate infusions

Serum methotrexate (MTX) levels were measured in 12 children (ages 2-18 years) who received a total of 56 24-h infusions of intermediate-dose methotrexate (500 mg/m2) at 1- to 3-week intervals. Mean peak serum MTX concentration 1/2 h following a bolus of 167 mg/m2 MTX (1/3 total dose) was 25.9 X 10(-6) M, mean plateau serum MTX concentration was 7 X 10(-6) M (over 8-24 h), and mean MTX clearance was 74 ml/min/m2. No significant changes in these values were noted with increasing number of infusions, suggesting that no metabolic adaptation occurred in the manner in which the body handled the MTX when it was given repeatedly in this fashion. However, adolescent patients (greater than or equal to 15 years) demonstrated a trend toward increased MTX clearance and decreased serum MTX concentration with greater than or equal to 5 infusions. In general, toxicity was minimal and did not increase with an increasing number of infusions. Significant toxicity was found only in adolescent patients, in spite of no documented difference in either MTX serum concentrations or clearance rates between adolescent and preadolescent patients.     

Relationships between ondansetron systemic exposure and antiemetic efficacy and safety in cancer patients receiving cisplatin.

Single concentration estimators of systemic exposure to the serotonin type 3 receptor antagonist and antiemetic, ondansetron, were established in 55 cancer patients receiving cisplatin-based chemotherapy plus a daily regimen of ondansetron given every 4 h for 3 doses on each day of chemotherapy. Ondansetron plasma concentration measured 4 h after the first daily dose of ondansetron (C[4h]) proved to be a reliable index of AUC and hence of systemic exposure. In patients receiving dosages of cisplatin < 95 mg/m2, the risk of emesis was greatest among those with the lowest systemic exposure to ondansetron. Most patients (64%) experienced emesis if C[4h] was < 20 ng/ml, whereas emesis did not occur in any patient with C[4h] > 80 ng/ml. Among patients receiving very high dosages of cisplatin (> 95 mg/m2), comparable levels of systemic exposure were not totally effective in preventing emesis. For these patients, more ondansetron was required to block the greater emetic stimulus produced by higher doses of cisplatin. This difference reflects a shift in the log exposure versus response relationship, and is consistent with serotonin antagonism at a receptor. In contrast, reported side effects of ondansetron were not related to exposure.     

An animal model for the study of chronopharmacokinetics of drugs and application to methotrexate and vinorelbine

An animal model was designed to study the chronopharmacokinetics of intravenous drugs and applied to anticancer agents vinorelbine (VNB) and methotrexate (MTX). Each experiment was performed on four pigs housed in a standardized light-dark cycle (12:12). Four pigs received a 0.16-mg bolus of VNB, followed by a 60-h continuous infusion at 0.48 mg/h. After hydration and urine alkalinization, four other pigs received a 2 mg/kg bolus of MTX, followed by two concomitant 60-h continuous infusions, one with MTX (8 mg/kg/h) and the other for hydration and folinic acid rescue (1.5 mg/kg/24 h). Serum cortisol was determined in each blood sample collected in these pigs. Blood samples were collected each hour for 60 h. The infusion flow rates and drug solution concentrations were controlled throughout the experiments. Analysis of VNB serum concentrations did not show any circadian rhythm of VNB serum concentrations. One pig administered MTX exhibited severe toxicity. Interestingly, no circadian rhythm of serum cortisol concentration was observed in this pig, whereas the three others exhibited a statistically significant cortisol circadian rhythm with a peak secretion in the morning. Two of these three pigs showed a significant 24-h rhythm of MTX with acrophase occurring at approximately 1:00 PM in both. The maximal concentration was found at 12:00 AM in the third pig. After the data were pooled, a highly significant (P < 0.01) circadian rhythm in MTX serum concentrations (57%) was found, with acrophase at midday. The pig represents a useful model for the study of chronopharmacokinetics of drugs given intravenously in human. The MTX chronokinetic variation found herein may be of interest for the improvement of chemotherapy in cancer patients.     

单剂量肌肉注射氨甲蝶呤治疗异位妊娠的药动学及药效学研究

目的:研究单剂量肌肉注射氨甲蝶呤(MTX)治疗异位妊娠(EP)的药动学及药效学,为给药方案的选择提供理论依据。方法:采用荧光偏振免疫分析法测定8名EP患者单剂量肌肉注射MTX50mg/m2后的血药浓度;观察血人绒毛膜促性腺激素(β-HCG)治疗前、后的变化和用B超检查异位妊娠包块的大小。结果:单剂量肌肉注射MTX后体内过程符合二室开放模型,服药后1.90h血药浓度达峰值,峰浓度为2.31μmol/L;治疗后β-HCG恢复正常时间为(24.8±10)d,有生育要求者的输卵管通畅率为75%。结论:治疗异位妊娠单剂量肌肉注射MTX50mg/m2有效。     

超大剂量甲氨蝶呤在骨肉瘤患者化疗中的血药浓度监测

目的对大剂量甲氨蝶呤（High dose methotrexate,HD-MTX）治疗骨肉瘤患者的血药浓度进行动态监测,并探讨其临床意义。方法采用均相酶免疫分析法对接受HD-MTX化疗的10例骨肉瘤患者按照需要定时测定甲氨蝶呤的浓度,分析各时间点MTX血药浓度特点及其与不良反应之间的关系。结果测得MTX0h平均峰浓度为（9.4737±3.9473）×10-4moL·L-1,72h平均峰浓度为（9.2743±5.0516）×10-8moL·L-1,其中2例的24hMTX血药浓度和1例48hMTX血药浓度大于中毒浓度,有两例出现毒副反应,对四氢叶酸钙（CF）加大剂量、延长用药时间后,症状消失,所有患者均未发生严重不良发应。结论不同患者MTX各时间点的浓度存在个体差异,应进行血药浓度监测。在血药浓度监测下,及时根据病人实际情况调整CF的解救时间与剂量,使HD-MTX治疗安全可行。     

Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients

The pharmacokinetics and bioavailability of low-dose methotrexate (MTX) (10 mg/m2) were evaluated in 41 subjects who had definite or classical rheumatoid arthritis as defined by the American Rheumatism Association criteria. Subjects received 10 mg/m2 (to the nearest 2.5 mg) of MTX in a single oral dose and a single intravenous (iv) dose one week apart. Serum concentrations for this low-dose regimen were monitored using a radiochemical ligand binding assay. The results indicate the MTX is cleared from the plasma at a rate of 84.6 mL/min/m2. The terminal half-life was approximately 6 h. The volumes of distribution at steady state and for the central compartment were 22.2 and 13.5 L/m2, respectively. The mean residence time in the body, in the systemic circulation, and in the periphery were estimated to be 4.7, 3.0, and 1.7 h, respectively, with a peripheral single-pass mean transit time of 6.0 h and an intrinsic mean residence time in the periphery of 7.9 h. The mean absorption time was 1.2 h and the oral bioavailability was 0.70. The ratio of synovial fluid concentration to serum concentration 4 and 24 h after a dose was found to be approximately 1.0, indicating that at least within that time range serum and synovial fluid concentrations are approximately equal. Because of conflicting results and insufficient data from previous high-dose pharmacokinetic studies, it is difficult to say whether or not low-dose MTX pharmacokinetics differs from those of high-dose MTX.     

Serum morphine concentration after oral administration of diamorphine hydrochloride and morphine sulphate.

1 Venous blood was obtained from patients with far-advanced cancer receiving either diamorphine (diacetylmorphine, heroin) hydrochloride (65 samples) or morphine sulphate (24 samples) regularly by mouth in doses from 2.5 mg to 90 mg every 4 h. 2 Samples were obtained within 30 min of the 09.00 h drug round. 3 Serial samples were also obtained over a 4 h period from three patients receiving diamorphine hydrochloride. 4 Assay of serum 'morphine equivalents' was by radioimmunoassay using an antibody that cross reacts almost equally with diamorphine, 6-0 monoacetylmorphine and morphine. 5 The serum concentration of opiates expressed as 'morphine equivalents' ranged from 11 ng/ml to 1440 ng/ml. 6 A highly significant positive linear correlation exists between the dose administered and the serum concentration (P less than 0.001) with respect to both drugs. 7 There was no difference between the two drugs in relation to the serum concentration achieved per 10 mg of opiate administered. 8 Higher oral doses of both diamorphine and morphine are now being used when indicated rather than, as before, resorting to injections when an oral dose in excess of 40 mg is indicated.     

The pharmacokinetics of midazolam in patients with congestive heart failure.

The disposition of midazolam was investigated in six patients with congestive heart failure (CHF) and six age- and weight-matched healthy subjects by administering two single doses of the drug (3.75 mg i.v. and 7.5 mg p.o.) separated by 1 week. Serial blood samples were collected for 24 h after each dose and plasma was assayed for midazolam by GC-MS. In the CHF patients, the elimination half-life was prolonged (4 to 4.5 vs less than 3 h), the systemic clearance was lowered (376 vs 551 ml min-1) and the peak plasma drug concentration after the p.o. dose was higher (76 vs 42 ng ml-1). The systemic availability (45 vs 41%), the steady state volume of distribution (111 vs 108 l) and the time of peak plasma drug concentration after the p.o. dose (0.9 vs 0.9 h) were unchanged. The predominant effect of CHF was on the clearance of midazolam which was decreased by 30%. The drug was well tolerated and did not cause any adverse effects.     

急性淋巴细胞白血病患儿甲氨蝶呤化疗中血药浓度的监测

目的:通过血药浓度监测,提高对小儿急性淋巴细胞白血病大剂量甲氨蝶呤化疗的有效性和安全性。方法:以接受55次1.5~4.0g/m2的大剂量甲氨蝶呤化疗的27例急性淋巴细胞白血病患儿为研究对象,定时采血测定甲氨蝶呤血药浓度,根据甲氨蝶呤静脉滴注结束时(12h)血药浓度评价化疗的有效性,根据甲氨蝶呤消除末端血药浓度决定四氢叶酸钙救援方案。结果:2.0、3.0、4.0g/m2剂量组的甲氨蝶呤静脉滴注结束时(12h)血药浓度维持在渗透浓度(2×10-5mol/L)以上的化疗次数分别占75%、92.1%、100%;仅1例患儿出现大面积皮肤粘膜损伤,其余无不可逆的严重不良反应发生。结论:进行甲氨蝶呤血药浓度监测有利于掌握好甲氨蝶呤和四氢叶酸钙的救援剂量,从而保证化疗的有效性和安全性。