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1.
非诺贝特缓释片人体药代动力学及生物等效性研究 总被引:2,自引:1,他引:2
目的研究非诺贝特缓释片在健康男性志愿者体内的药动学特征及生物等效性。方法20名健康男性志愿者双交叉单次服用0.25g非诺贝特缓释片和非诺贝特缓释胶囊,24名健康男性志愿者双交叉连续服用非诺贝特缓释片和非诺贝特缓释胶囊6d,用HPL-UV测定血浆中的非诺贝特酸浓度,比较单次用药和多次连续用药后体内非诺贝特酸的药代动力学参数,采用DAS2.0进行两制剂的生物等效性检验。结果20名健康男性志愿者双交叉单次服用0.25g非诺贝特缓释片和非诺贝特缓释胶囊后,体内的主要药代动力学参数tmax为(5.25±1.27)h,(4.93±0.71)h;Cmax为(8.58±2.77)mg·L^-1,(9.75±3.44)mg·L^-1;AUC0-96为(188.34±65.66)mg·h^-1·L^-1,(194.02±56.58)mg·h^-1·L^-1。24名健康男性志愿者双交叉连续服用非诺贝特缓释片和非诺贝特缓释胶囊6d后体内的主要药代动力学tmax为(5.06±0.92)h,(5.04±0.93)h;C。,为(7.25±2.32)mg·L^-1,(8.03±3.27)mg·L^-1;AUCss为(174.06±55.67)mg·h^-1·L^-1,(192.66±78.53)mg·h^-1·L^-1。结论连续用药6d体内达到稳定血药浓度,单次用药和多次用药后主要药代动力学参数相似,体内无明显蓄积现象。非诺贝特缓释片和胶囊单次用药和多次用药后均显示生物等效。 相似文献
2.
建立了HPLC法测定人血浆中非诺贝酸。以苄普地尔为内标,采用C18柱,流动相为甲醇-水-10%磷酸(70∶30∶1),检测波长286nm。非诺贝酸在0.1~25μg/ml浓度范围内线性关系良好,方法回收率96.8%~105.0%。24名男性志愿者单剂量口服非诺贝特200mg的药物动力学参数Tmax、Cmax、t1/2和AUC0→∞分别为(6.02±2.56)h、(5.33±3.81)μg/ml、(23.61±5.98)h和(169.75±126.96)μg·h·ml-1。 相似文献
3.
4.
Summary The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 µg/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On Day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs. 相似文献
5.
肾移植术后早期国产环孢素药动学的临床研究 总被引:4,自引:0,他引:4
目的:探讨肾移植受者术后早期服用国产环孢素的药动学变化特点。明确环孢素各时点血药浓度与时间-曲线下面积(AUC)的相关关系。方法:43例肾移植受者始服环孢素6 mg·kg~(-1)·d~(-1)7 d后,按不同品种分A组18例,B组15例,C组10例。3组分别于服药即刻,服药后1,2,3,4,5,6,8,10,12 h抽血查环孢素浓度(以C_0、C_1、C_2……C_(12)表示),比较不同品种药动学的变化特点。然后,用逐步回归分析法计算环孢素的总体C_0、C_2、峰浓度C_(max),达峰时间(T_(max)),AUC以及各种指标的变异系数,并计算各浓度值与AUC的相关关系。结果:3种国产环孢素在使用相同剂量时,C_0,C_2,C_(max),T_(max),AUC差异均无显著性,具有同质性。合并分析后,总体值C_0为(215.2±113.0)μg·L~(-1),总体C_(max)=C_2为(1024.8±378.7)μg·L~(-1),达峰时间(2.0±0.9)h,平均2h,AUC为(5106.4±1471.8)μg·h·L~(-1)。抽血检测的10个时点浓度中,C_1、C_2、C_3、C_4、C_6与AUC的相关性有显著性,其中C_2偏相关系数0.96最大,而变异系数(34.9%)相对较小。C_0不仅变异系数(52.8%)较大,且与AUC的相关性亦不显著。结论:国产环孢素总体峰浓度为C_2,与AUC具有较好的相关性,对AUC的变化影响大。可以将C_2作为临床一个常规的环孢素浓度监测指标。 相似文献
6.
目的了解心脏移植术后患者环孢素(CsA)血药浓度变化和排斥反应、不良反应发生情况,并探讨其相关性。方法收集2010年1月至2011年12月在北京安贞医院行心脏移植术患者的病历资料进行回顾性分析,记录患者的一般情况、CsA血药浓度监测情况以及排斥反应和不良反应发生情况,分析CsA全血谷浓度(C0)和峰浓度(C2)与排斥反应和不良反应的关系。结果纳入分析的27例患者中男性24例,女性3例,平均年龄 (38±14)岁,平均身高 (170±10) cm,平均体重 (68.0±15.8) kg。原发疾病:扩张性心脏病18例,冠状动脉粥样硬化性心脏病4例,瓣膜性心肌病3例,心律失常性右心室心肌病1例,心肌致密化不全1例。术后早期(〈1个月)CsA血药浓度较低, 75例次C0检测中35例次(46.7%)、69例次C2检测中56例次(81.2%)低于有效浓度。C0在术后1~3个月升高, 4个月后逐渐降低,7个月后逐渐趋于稳定。C2在术后1~3个月升高,4个月后逐渐降低,13个月后略有回升。27例患者中有9例(33.3%)发生排斥反应,8例为急性排斥反应,发生在术后4~12个月,主要表现为乏力、食欲不振、活动后心悸、烦躁,其中1例死亡;1例为慢性排斥反应,发生在术后13个月,表现为心率增快和外周血淋巴细胞计数升高。27例中有7例(25.9%)出现肾功能损伤,发生在术后1个月内、3~6个月和7~12个月者分别为3、2、2例,主要表现为肌酐清除率下降,血清尿素、肌酐、钾升高和高尿酸血症;1例(3.7%)在术后2个月出现肝功能损伤,主要表现为丙氨酸转氨酶(ALT)和总胆红素(TBil)升高;18例(66.7%)出现总胆固醇 (TC)、低密度脂蛋白胆固醇 (LDL-C) 和三酰甘油 (TG) 升高,发生在术后3个月内和7~12个月者分别为17和1例;10例(37.0%)出现空腹血糖升高,发生在术后1个月内、4~12个月和18个月者分别为7、2和1例。未出现急性排斥反应者CsA的C0及C2均明显高于出现急性排斥反应者[(216±90) μg/L比(167±103) μg/L,(718±297) ng/ml比(472±251) μg/L,均P〈0.01]。出现不良反应者C0及C2均明显高于未出现不良反应者[(241±93) μg/L比(190±95) μg/L,(837±314) μg/L比(596±283) μg/L,均P<0.01]。CsA的C0与血清尿素、肌酐和空腹血糖相关(r=0.359,P=0.000;r=0.170, P=0.014; r=0.164, P=0.018),C0与C2均与TBil、TC和LDL-C相关(r=0.182, P=0.009; r=-0.170, P=0.018; r=0.267, P=0.001; r=0.320, P=0.000; r=0.251, P=0.001; r=0.275, P=0.000)。结论心脏移植术后患者CsA血药浓度与排斥反应和不良反应的发生密切相关,进行CsA血药浓度监测有利于及时调整CsA剂量,降低排斥反应和不良反应发生率。 相似文献
7.
8.
人血浆中非诺贝特活性代谢物非诺贝酸的高效液相色谱法测定 总被引:8,自引:0,他引:8
目的 :建立快速测定人血浆中非诺贝特活性代谢物非诺贝酸 (fenofibricacid)的高效液相色谱方法。方法 :以乙腈 - 1mol·L-1盐酸 (95∶5 )直接沉淀血浆蛋白 ,色谱柱为配有Waters保护柱的YWG -ODS 10 μm 2 0 0mm× 4 0mm ,流动相为甲醇 -水 - 10 %磷酸 (76∶2 4∶1) ,检测波长 2 86nm ,外标法峰高定量。结果 :非诺贝酸的保留时间约为 4 4min ,定量线性范围 0 2 5~ 18 75 μg·mL-1,绝对回收率大于 85 % (n =5 ) ,方法回收率大于 90 % (n =5 ) ,日内日间RSD小于 10 % (n =5 )。结论 :本法简便快速、定量准确 ,适用于非诺贝特键康人体临床药代动力学研究 相似文献
9.
A. Lindholm 《European journal of clinical pharmacology》1991,40(6):571-575
Summary The free fraction of cyclosporine A (CsA) and its total plasma concentration as determined by HPLC(CsAT) were prospectively monitored in 66 recipients of renal transplants. The free CsA levels (CsAu) were calculated.The variability in free CsA levels was no less than for total CsAT levels. The correlation between CsAu and CsAT was high (r=0.90). Both CsAT and CsAu covaried with serum triglycerides and apolipoprotein A1.Fourty-four of the 66 patients suffered acute rejection episodes on 69 occasions. CsAT and CSAu both decreased and to a similar extent at the occurrence of acute rejection (42% and 59% decrease, respectively; significant vs baseline. Notsignificant difference in decrease in CsATvsCsAu).Acute nephrotoxicity occurred on 11 occasions in 10 patients. Both CsAT and CSAu were approximately twice as high at the time of acute nephrotoxicity as compared to one week previously. Both CsAT and CsAu were higher during the first month after transplantation in patients with than in patients without systemic infection.Thus, plasma CsAu gave no additional clinical information or guidance compared to CsAT in renal transplant recipients. Due to the complexity of its assay, which requires two consecutive analyses, there does not appear to be any need for routine monitoring of CsAu in renal transplant recipients. 相似文献
10.
Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine 总被引:1,自引:0,他引:1
J. K. Madsen J. D. Jensen L. W. Jensen E. B. Pedersen 《European journal of clinical pharmacology》1996,50(3):203-208
Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive
felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between
the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine,
and cyclosporine, and 24-hour blood pressure measurements.
Methods:
Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were
given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake.
Results:
For cyclosporine, Cmax was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic
parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and Cmax (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite
dehydrofelodipine, too, AUC and Cmax were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures
were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine
(122/68 mmHg) compared to cyclosporine alone (127/73 mmHg).
Conclusion:
A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and Cmax of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine
was only slightly increased by felodipine.
Received: 28 August 1995/Accepted in revised form: 18 December 1995 相似文献
11.
肝移植术后环孢素治疗药物监测 总被引:3,自引:1,他引:3
目的:研究肝移植受者环孢素A临床药动学特点,优化环孢素A治疗药物监测方案。方法:采用荧光偏振免疫法测定环孢素A血药浓度,计算临床药动学参数。建立AUC0-12h与浓度变量回归模型。对C0、C2常规监测数据进行分析。结果:环孢素代谢呈二房室开放模型。C0 C2与AUC0-12h相关较为强烈,C2与AUC0-4h和AUC0-12h的相关性高于C0。在估算AUC0→12h的回归模型中,C0 C2最好,SE和R-sq分别为501.0和94.7,其后是C6,C2,C9,C4和C0。结论:环孢素A临床药动学个体差异大。C0 C2两点监测是环孢素A最好的监测方法,可客观评价环孢素A体内药物暴露(AUC0-12h),减少急性排斥和药物中毒发生。C2/C0可以作为评价移植肝功能恢复的灵敏指标。 相似文献
12.
C. W. Maboundou G. Paintaud C. Vanlemmens J. Magnette S. Bresson-Hadni G. Mantion J. P. Miguet P. R. Bechtel 《European journal of clinical pharmacology》1996,50(4):335-337
Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability.
Methods:
Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg)
with placebo in single doses. Blood concentrations of CsA were measured by HPLC.
Results:
There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml–1, Cmax was 832 vs 871 ng⋅ml–1 and tmax was 2 vs 2 h, after ursodiol and placebo, respectively.
Conclusion:
Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption
in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely.
Received: 19 October 1995/Accepted in revised form: 8 January 1996 相似文献
13.
目的:探讨心脏移植患者术后口服免疫抑制剂环孢素的血药浓度与PXR基因多态性的相关性。方法:应用飞行时间质谱技术对59例心脏移植术后稳定期患者的PXR基因型进行检测,全自动化学免疫分析仪测定环孢素的血药浓度,并通过统计学分析PXR各单核苷酸多态性(SNP)位点基因型对环孢素血药浓度的影响。结果:PXR基因筛选出的8个Tag SNP位点次要等位基因频率(MAF)与NCBI的dbSNP数据库中中国人的数据相近。对于59名稳定期心脏移植患者PXR基因8个Tag SNP中,仅携带PXR rs1523127(C 24381 A)位点AA型基因的患者血药浓度及校正血药浓度明显低于CA型,CA型又低于CC型患者,差异均具有统计学意义(P<0.05)。其他7个Tag SNP rs3814056T>G、rs7643645A>G、rs11917714C>T、rs2276705C>A、rs2472681T>C、rs2472682C>A、rs4440154C>T各基因型组间环孢素血药浓度的差异均无统计学意义。结论:PXR rs1523127(C 24381 A)基因型与心脏移植稳定期患者环孢素血药浓度显著相关,提示该SNP可能会在环孢素个体化用药中发挥重要作用。 相似文献
14.
目的:建立同时测定大鼠在体肠循环液中非诺贝特和非诺贝酸的方法。方法:采用高效液相色谱法,色谱柱为Kro-masil C18柱(150 mm×4.6 mm5μm),流动相为甲醇-水(80∶20),pH3.0,柱温为室温,流速1.0mL.min-1,检测波长286 nm。结果:非诺贝特、非诺贝酸分别在0.25~124.68 mg.L-1、0.01~5.05 mg.L-1范围内与峰面积呈良好线性关系,r分别为0.999和0.999 9。其平均回收率分别为98.83%、101.13%,RSD均小于4%。结论:该法操作简便、结果准确、灵敏度高,可同时测定大鼠在体肠循环液中非诺贝特和非诺贝酸的含量。 相似文献
15.
反相高效液相色谱法测定家兔非诺贝特酸的血药浓度 总被引:4,自引:0,他引:4
目的:建立HPLC法测定家兔血浆中非诺贝特酸的血药浓度。方法:以吲哚美辛为内标,甲醇-0.02 mol·L~(-1)醋酸盐缓冲液pH3.6(63:37)为流动相,检测波长为296nm。结果:低、中、高浓度的日内回收率分别为97.02%,97.66%,101.17%,RSD分别为1.41%,4.27%,1.01%;日间回收率分别为96.32%,93.51%,95.60%,RSD分别为4.91%,4.70%,3.46%。结论:该法操作简便,结果可靠,适用于非诺贝特酸家兔血药浓度的测定。 相似文献
16.
目的评价环孢素A胶囊与他克莫司胶囊治疗肝移植受体排斥的经济性。方法选择在我院接受肝移植,并于2010年1月-2011年12月在门诊继续治疗的患者共60例,比较用药半年后的临床疗效、不良反应及用药成本,运用药物经济学的最小成本分析法对两种药物的经济效果进行评价。结果环孢素A胶囊组总有效率为78%,他克莫司胶囊组为86%,两组比较差异无统计学意义(P>0.05),环孢素A胶囊组的不良反应发生率较他克莫司胶囊组低。成本/效果比(C/E):环孢素A胶囊组为55.81,他克莫司胶囊组为46.19。结论与环孢素A胶囊比较,他克莫司胶囊用于肝移植受者更为经济有效。 相似文献
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18.
Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients 总被引:1,自引:0,他引:1
Fatemeh Akhlaghi rew J. McLachlan Anne M. Keogh & Kenneth F. Brown 《British journal of clinical pharmacology》1997,44(6):537-542
Aims To investigate the effects of lipid lowering therapy on the fraction unbound and dosage requirement of cyclosporine in heart transplant recipients.
Methods Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months before and after simvastatin administration. The total number of dose rate-concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P-PHARM software) the ratio of dose rate to trough concentration at steady state (DR/Csstrough ), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/Csstrough was calculated for each patient before and after simvastatin administration.
Results The mean fu increased by 29%, from 1.40±0.1% (mean±s.d.) to 1.82±0.22% after simvastatin administration (P<0.01). Mean trough concentrations of cyclosporine in whole blood were 349 μg l−1 before and 242 μg l−1 after simvastatin administration (P<0.0001). The mean cyclosporine daily dosage was 2.87 mg kg−1 and 2.33 mg kg−1 (NS), before and after simvastatin administration respectively. The average cyclosporine DR/Csstrough was significantly increased from 24.5 l h−1 before to 28.9 l h−1 after simvastatin administration (P<0.05). Furthermore the median increase in cyclosporine DR/Csstrough was 18 l h−1 (−3.1 to 42.1 l h−1, interquartile range).
Conclusions Cyclosporine fraction unbound and clearance are increased following co-administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine. 相似文献
19.
《Expert opinion on drug safety》2013,12(1):145-156
Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug–drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination. 相似文献
20.
目的:确定长期存活的肾移植术后患者环孢素 A(CsA)的治疗窗.方法:将已存活4a以上的39例肾移植患者763个血浓谷值按术后时间分为7组,按肝肾功能指标分为3组进行比较分析.结果:肾移植患者的全血CsA谷值(多克隆)维持浓度随着术后时间的延长而降低,肾移植患者各个时期CsA较适宜的治疗窗为:450~600ng/ml(0~6mo),400~550 ng/ml(6~12mo),350~500 ng/ml(1~3a),300~450ng/ml(3~5a),250~40Ong/ml(5~7a).结论:肾移植患者的全血CsA谷值维持浓度随术后时间延长而降低. 相似文献