来氟米特在中国健康人群中的群体药动学研究

目的：建立来氟米特口服给药在中国健康受试者体内的群体药动学模型,探讨其药动学特征及可能的影响因素。方法：21名健康男性受试者参与本次研究,应用Phoenix NLME（Vision 8.0）软件中的群体模块分析来氟米特口服给药后其代谢产物的血药浓度数据,估算相关药动学参数及其变异情况。结果：来氟米特活性代谢产物特立氟胺在健康志愿者中符合一级吸收的一室模型。吸收速率常数K_a、分布容积V、药物清除率CL的群体典型值分别为0.691 h^-1、12.843 L和0.031 L·h^-1。协变量筛选结果显示,BMI对分布容积V有显著影响（P<0.01）。结论：本研究成功建立了来氟米特在中国健康人群中的群体药动学模型,最终模型可对个体药代参数做出精确的估计,BMI对分布容积V有显著影响。     

The pharmacokinetics of ofloxacin in healthy adult male volunteers

Conclusion In healthy subjects ofloxacin pharmacokinetics were found to be linear in the dose range studied (100–400 mg). The terminal half-time was 7.5–8 h and plasma ofloxacin concentrations were still detectable at 16 and 24 h after administration. The ratio of renal ofloxacin clerance: creatinine clearance was 1.35–1.82 and was not significantly different for the three doses. The non-renal clearance of ofloxacin was 40–60 ml·min^–1, i.e. 20–30% of the total body clearance.Food intake delayed the absorption of ofloxacin but did not significantly modify its elimination.     

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers

Summary The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg·kg^–1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg·kg^–1 i.v. of dlsotalol.There was no significant difference in the disposition of the d-enantiomer and the racemate.The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l·h^–1·kg^–1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).     

A review of the pharmacokinetics,tolerability and pharmacodynamics of amisulpride in healthy volunteers

Amisulpride binds selectively to dopamine D(2) and D(3) receptors in the limbic system. Low doses of amisulpride preferentially block presynaptic D(2)/D(3)-dopamine autoreceptors, thereby enhancing dopaminergic transmission, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. Amisulpride is clinically effective on the negative symptoms of acute schizophrenia exacerbations at low dosages (50-300 mg/day), and also on the positive symptoms of the disease at high dosages (400-800 mg/day). Nineteen clinical studies involving 358 volunteers have investigated the pharmacokinetics, pharmacodynamics and tolerability of amisulpride. Amisulpride shows linear pharmacokinetics, a bioavailability of 48%, low protein binding (17%) and an elimination half-life of approximately 12 h. It is predominantly eliminated in the urine as the parent compound. It exhibits no significant detrimental effects in psychometric or memory tests up to the dose of 400 mg/day, inducing only mild impairment at high doses, whereas EEG data suggest an alertness-enhancing effect at low doses (相似文献   

Tolerance and pharmacokinetics of single-dose intravenous hemoporfin in healthy volunteers

Aim:

To investigate the safety, tolerability and pharmacokinetics of intravenous hemoporfin, a novel photosensitive drug for the treatment of port-wine stain (PWS), in healthy Chinese volunteers following single-dose administration.

Methods:

Thirty-six healthy Chinese subjects were enrolled. The subjects were administered hemoporfin (2.5, 5, 7.5 or 10 mg/kg) via single-dose intravenous infusion. Pharmacokinetics of the drug were studied in the groups with doses of 2.5, 5 and 7.5 mg/kg, and tolerability was studied in all the 4 groups. Safety and tolerance were evaluated by monitoring adverse events and laboratory parameters, and pharmacokinetics were assessed by determining hemoporfin content with a validated high-performance liquid chromatography with fluorescence detection (HPLC/FLD) method.

Results:

Mild and transient adverse events occurred in the trial (n=10), but none were serious, and no subjects were withdrawn from the trial. The gastrointestinal tract adverse events, such as nausea, stomach upset, abdominal pain and vomiting, were observed in the groups with doses of 7.5 and 10 mg/kg. Increased alanine aminotransferase (ALT) concentration was found in 3 subjects, and increased alkaline phosphatase (ALP) concentration in one subject. The half-life of hemoporfin for doses of 2.5, 5, and 7.5 mg/kg was 1.26 h, 1.31 h, and 1.70 h, respectively. C_max and AUC increased with dose for intravenous single-dose administration of hemoporfin in the 2.5, 5, and 7.5 mg/kg groups. Urinary excretion of hemoporfin within 12 h was less than 0.2%.

Conclusion:

Hemoporfin is safe and well-tolerated in healthy Chinese volunteers at a single intravenous dose of up to 10 mg/kg. It was rapidly cleared from the blood and had a short half-life, which insures a short light-avoidance period.     

Population pharmacokinetics of arginine glutamate in healthy Chinese volunteers

1.?The present study developed population pharmacokinetic models of arginine and glutamate in healthy Chinese volunteers. Two nonlinear mixed-effect models were developed using NONMEM® software (ICON Development Solutions, Ellicott City, MD) to describe the pharmacokinetic properties and to assess the relevant parameters as well as the inter-individual variability. The potential covariates were screened using stepwise approach and the stability and predictive capability of the models were performed using bootstrap and visual predictive check.

2.?The concentration time curves of arginine and glutamate were best described by a first-order elimination two-compartment model and a nonlinear elimination one-compartment model, respectively. The final parameter estimation of arginine for CL was 44.1?L/h. Q, V₁ and V₂ were 23?L/h, 20.3?L and 46?L, respectively. The final parameter estimation of glutamate for V_max and K_m were 18.8?mg/h and 77.2?mg/L, respectively. V for low dose and high dose was 23.1?L and 36.3?L, respectively.

3.?For arginine, weight was significant covariate on the apparent distribution volume of peripheral compartment. The gain in weight remarkably increases V_2. For glutamate, dose as a significant covariate on the apparent distribution volume was included, subjects received high dose (20?g) have remarkably higher V compared to subjects received low dose (10?g).     

合用盐酸黄连素前后环孢素A的人体药动学

目的 :研究健康受试者合用盐酸黄连素 (berberinehydrochloride ,Ber)前后环孢素A(cyclosporinA ,CsA)的动力学过程 ,以分析两药相互作用发生的部位。方法 :6名健康男性志愿者在单剂口服CsA 3mg·kg-1后开始连续服用Ber 30 0mg ,bid× 10d ,最后一次与单剂CsA 3mg·kg 　 -1同时口服。每次口服CsA后即按时采血 ,用FPIA法测定全血CsA浓度 ,并计算出药动学参数。结果 :在健康志愿者合用Ber后 ,CsA的AUC值增加 19.6 % ,差异具非常显著性 (P <0 .0 1)。结论 :推测Ber对CsA的影响部位可能主要在肠道 ,Ber可能增加CsA的吸收或减少肠代谢。     

Single dose pharmacokinetics of sumatriptan in healthy volunteers

Sumatriptan is classified as a vascular 5HT₁ receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration.The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration.Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h.Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.     

Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers

Influence of fluconazole on the pharmacokinetics of omeprazole was evaluated by single oral administration of omeprazole capsule 20 mg (control group), or single oral administration of fluconazole capsule, 100 mg, and omeprazole, 20 mg, after 4 days of daily oral administration of fluconazole, 100 mg (treated group), to 18 healthy male volunteers. Omeprazole is extensively metabolized in the liver through 5-hydroxylation and sulfoxidation reactions catalyzed predominantly by CYP2C19 and CYP3A4, respectively. Fluconazole is a potent competitive inhibitor of CYP2C19 and a weak inhibitor of CYP3A4. In treated group, the area under the plasma concentration-time curve of omeprazole from time zero to time infinity (AUC) was significantly greater (3090 vs 491 ng h/ml), terminal half-life of omeprazole was significantly longer (2.59 vs 0.85 h), and peak plasma concentration of omeprazole (C(max)) was significantly higher (746 vs 311 ng/ml) than that in control group. The greater AUC and higher C(max) in treated group could be due to inhibition of omeprazole metabolism by fluconazole.     

The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous,intramuscular, and subcutaneous injection

Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 g lisuride hydrogen maleate as an aqueous solution.After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min^–1·kg^–1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration.The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.     

Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers

AIM: To assess the effect of Schisandra sphenanthera extract (SchE) on the pharmacokinetics of tacrolimus in healthy volunteers. METHODS: Twelve healthy male volunteers were orally treated with SchE, three capsules twice daily for 13 days. Pharmacokinetic investigations of oral tacrolimus administration at 2 mg were performed both before and at the end of the SchE treatment period. Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters before and with SchE were calculated with noncompartmental techniques. RESULTS: Following administration of SchE, the average percentage increases of individual increases in AUC, AUMC and C(max) of tacrolimus were 164.2% [95% confidence interval (CI) 70.1, 258.4], 133.1% (95% CI 49.5, 261.3) and 227.1% (95% CI 155.8, 298.4), respectively (P < 0.01 or 0.05). On average, there was a 36.8% (95% CI 13.4, 60.2) increase in tacrolimus t(max) (P < 0.01). The average percentage decreases in CL/F and V/F were 49.0% (95% CI 31.1, 66.9) and 53.7% (95% CI 40.1, 67.4), respectively (P < 0.01). CONCLUSIONS: SchE can increase the oral bioavailability of tacrolimus. The results of this study will add important information to the interaction area between drugs and herbal products.     

Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers

AIMS

To assess the effect of Schisandra sphenanthera extract (SchE) on the pharmacokinetics of midazolam, a probe drug of CYP3A, and its metabolite 1′-hydroxy midazolam in healthy volunteers.

METHODS

Twelve healthy male volunteers were orally treated with SchE, three capsules twice daily for 7 days. Pharmacokinetic investigations of oral midazolam administration at 15 mg were performed both before and at the end of the SchE treatment period. The plasma midazolam and 1′-hydroxy midazolam concentrations were determined by high-performance liquid chromatography–tandem mass spectrometry. Estimated pharmacokinetic parameters before and with SchE were calculated with noncompartmental techniques.

RESULTS

Following administration of SchE, the average increases (%) of individual increases in AUC, AUMC and C_max of midazolam were 119.4% [95% confidence interval (CI) 83.9, 155.0], 183.4% (95% CI 120.5, 246.2) and 85.6% (95% CI 14.4, 156.9), respectively (P < 0.01 or 0.05). On average, there was a 133.3% (95% CI 8.9, 257.7) increase in midazolam t_max (P < 0.01). The average decrease (%) in CL/F was 52.1% (95% CI 44.9, 59.4) (P < 0.01). No significant changes were seen in midazolam half-life. After co-administration of SchE, the average increase (%) in t_max of 1′-hydroxy midazolam was 150.0% (95% CI 22.2, 277.8) (P < 0.05). No significant differences were observed in the other pharmacokinetic parameters of 1′-hydroxy midazolam.

CONCLUSIONS

SchE can markedly increase the oral bioavailability of midazolam in healthy volunteers. SchE is an inhibitor of CYP3A and has a high susceptibility to alter the disposition of drugs metabolized by CYP3A.     

阿昔洛韦片体内生物利用度研究

研究两种阿昔洛韦片药物动力学及生物等效性。采用反相高效液相色谱法 ( C18柱 ,流动相为 0 .1%醋酸溶液 ,流速 1.4 ml/min,测定波长 2 54nm)测定 10名志愿受试者单剂量口服 60 0 mg阿昔洛韦片后 ,阿昔洛韦血药浓度变化情况。结果表明供试品和参比制剂为生物等效制剂。药时曲线下面积分别是 :5.30± 1.19(μg· h) /ml与 5.4 1± 1.34 ( μg· h) /ml,达峰时间分别为 :1.84± 0 .55h与 1.97± 0 .39h,峰浓度分别是 :1.0 9± 0 .18μg/ml与 1.0 6± 0 .2 2 μg/ml。     

水飞蓟宾胶囊在中国健康志愿者体内的药代动力学研究

目的研究健康志愿者单剂量口服水飞蓟宾胶囊后水飞蓟宾的药代动力学。方法9名健康男性志愿者按拉丁方设计分别口服3种剂量水飞蓟宾胶囊(2粒、4粒和8粒,相当于水飞蓟宾70mg、140mg和280mg)。采用高效液相色谱(HPLC)法测定人血浆中水飞蓟宾的含量。应用Topfit2.0软件计算主要药代动力学参数。结果在所建的方法下,水飞蓟宾在3.125～10000μg.L-1的血浆浓度范围内线性关系良好,最低定量浓度为3.125μg.L-1。在3个给药剂量下水飞蓟宾的主要药代动力学参数分别为:T12为2.44、2.38、2.47h;Cmax为;1135.6、2841.1、3946.9μg.L-1;Tmax为1.35、1.26、1.39h;AUC0～11h为1287.2、3337.8、5398.5μg.h.L-1;AUC0-∞为1300.7、3377.1、5453.9μg.h.L-1;CL/F为1062.1、824.7、943.2ml.min-1;Vd为219.9、167.1、212.0L。结论所建的方法具有灵敏度高、准确性好、操作简便等优点,能够满足水飞蓟宾在人体内的药代动力学研究要求。3个剂量下水飞蓟宾在人体内的T12差异无统计学意义,Cmax、AUC0-11h与AUC0-∞3个药动学参数随给药剂量的增加呈非比例上升趋势。     

Dose-dependent pharmacokinetics of aprindine in healthy volunteers

Summary The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t_1/2) increased from 8.0±2.1 h (SD) after a 25 mg dose to 9.4±2.9 h after 50 mg and to 15.8±2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (V_dss/F) and during -phase (V_d/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (C_max) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t_1/2 after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.     

合用盐酸黄连素前后环孢素A的健康人体药动学研究

目的 :研究健康受试者合用盐酸黄连素 (Ber)前后环孢素A(CsA)的动力学过程 ,以分析两药相互作用发生的部位。方法 :6名健康男性志愿者在单剂口服CsA (6mg·kg-1)后开始连续服用Ber 13d(30 0mg·bid-1) ,然后再单剂口服CsA (6mg·kg-1) ,每次口服CsA后即按时采血 ,并用FPIA法测定全血CsA浓度 ,并计算出药动学参数。结果 :合用Ber前后CsA的主要药动学参数Ka 分别为 0 .91± 0 .30h-1和 1.0 9± 0 .35h-1;T1 2 β分别为 6.18± 0 .94h和6.86± 1.2 7h ;AUC0 -2 4 分别为 11.0± 1.6和 10 .6±1.6mg·h-1·L-1;CL(s)分别为 34.3± 6.7L·h-1和36.6± 9.3L·h-1;Tpeak均为 1.5± 0 .6h ;Cmax分别为1.8± 0 .4mg·L-1和 1.9± 0 .3mg·L-1。结论 :在健康志愿者合用Ber前后CsA的药动学参数没有显著差异 ,推测Ber对CsA的影响部位可能主要在肠道。     

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers

Summary We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 g·kg^–1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing.All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 g·kg^–1).Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (<20%) systemic clearances and larger values of C_max and AUC.Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 g·kg^–1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 g·kg^–1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 g·kg^–1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.     

老年患者和肾病患者口服阿替洛尔片的药物动力学研究

目的：测定阿替洛尔片的血药浓度，对健康壮年，老年及肾病志愿者进行药物动力学研究。方法；健康壮年及老年志愿受试者各８例，肾病志愿者５例，均为单剂量口服阿替洛尔片７５ｍｇ，用ＨＰＬＣ法测定。结果；药－时曲线符合一级吸收二室模型。健康壮年人的主要药动不参数为Ｋａ：１．０１ｈ＾－１，Ｔ１／２β：４．２８ｈ，Ｋ１０：０．２５ｈ＾－１，ＡＵＣ：５．２μｇ．ｈ．ｍｌ＾－１，ＣＬ／Ｆ：１４．９５ｍｇ．ｍｌ（μｇ．     

Multiple dose pharmacokinetics of tiludronate in healthy volunteers

Objectives: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. Methods: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. Results and conclusions: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (C_min) ranged between 0.19 and 1.5 mg ⋅ l⁻¹, and maximal plasma concentrations (C_max) between 1.1 and 7.8 mg⋅l⁻¹ for the lowest and highest doses, respectively. A supra-proportional increase in C_max, AUC₂₄ and A^e ₂₄ with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in C_max and AUC₂₄ with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D₃ and intact PTH (1–84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way. Received: 11 September 1995/Accepted in revised form: 28 March 1996     

The pharmacokinetics of intravenous,intramuscular, and subcutaneous nalbuphine in healthy subjects

Summary The pharmacokinetics of intravenously, intramuscularly, and subcutaneously administered nalbuphine were studied in three parallel groups of 12 healthy volunteers each. The subjects received single doses of 10 mg and 20 mg of nalbuphine separated by a one week washout period. Blood specimens were obtained up to 15 h after dosing for determination of nalbuphine.Mean plasma nalbuphine concentrations 5 min after intravenous administration of 10 or 20 mg were 39 and 73 ng/ml, respectively. The mean maximum plasma concentrations (C_max) after intramuscular or subcutaneous administration of nalbuphine 10 mg were 29 and 31 ng/ml, respectively. Mean C_max values after 20 mg doses were 60 and 56 ng/ml. Mean C_max occurred 30 to 40 min after nalbuphine administration. The mean elimination half-lives of parenterally administered nalbuphine ranged between 2.2 and 2.6 h, regardless of dose given or route administered. The mean absolute bioavailability was 81% and 83% for the 10 and 20 mg intramuscular doses, respectively, and 79% and 76% following 10 and 20 mg of subcutaneous nalbuphine. The mean volumes of distribution (V_ss) of the intravenously administered drug were 290 and 274 l and the mean systemic clearances were 1.6 and 1.5 l/min following administration of 10 and 20 mg doses, respectively.Intramuscular and subcutaneous nalbuphine appear to be interchangeable based on the similarities in C_max, mean times until maximum concentration, mean AUC data, and absolute bioavailabilities.