Absorption kinetics of cyclosporine in healthy volunteers

The absorption kinetics of cyclosporine were studied in eight healthy volunteers following oral and intravenous administration. Bioavailability of cyclosporine was observed to be 20.8 +/- 5.5 per cent. Absorption of cyclosporine was found to be better described by first order processes rather than by a zero order process as previously reported.     

Pharmacokinetics and safety of viramidine, a prodrug of ribavirin, in healthy volunteers

Ribavirin, part of the current first-line combination therapy for the treatment of chronic hepatitis C, has side effects-in particular, hemolytic anemia-that is frequently dose limiting. Based on animal studies, viramidine, a prodrug of ribavirin, is converted to ribavirin in the liver. Viramidine dosing yielded 50% higher ribavirin levels in the monkey liver but only half in plasma and red blood cells compared to ribavirin dosing. At the same dose, it also had a safer profile than ribavirin in a 28-day toxicity study in monkeys. The current study was carried out to evaluate the safety, tolerability, and pharmacokinetics of viramidine in healthy male volunteers (n = 8-18 on viramidine vs. 2 on placebo at each dose level) after oral dosing of viramidine at 200, 600, and 1200 mg. There were no serious adverse events, and most adverse events were mild. The percentages of treatment-emergent events judged to be possibly related to the study drug were 50% in the 1200-mg group, 26% in the 600-mg group, and none in the 200-mg group. Viramidine was orally absorbed and rapidly converted to ribavirin with a t(max) of 1.5 to 3.0 hours for both viramidine and ribavirin in plasma. There was dose proportionality in plasma AUC(0-168 h) and C(max) for viramidine and in plasma AUC(0-168 h) for ribavirin. Plasma AUC(0-168 h) for ribavirin was two to four times higher than plasma AUC(0-168 h) for viramidine, indicating that viramidine is extensively metabolized to ribavirin and is a prodrug of ribavirin in man. Amounts of viramidine and ribavirin excreted in the urine were small (2%-5% of dose), indicating that the main route of elimination for both viramidine and ribavirin is metabolism. Both viramidine and ribavirin were excreted into urine through the mechanism of glomerular filtration. In addition, an evaluation of the effect of a high-fat meal on the pharmacokinetics of viramidine and ribavirin after oral dosing of viramidine at 600 mg was conducted in healthy male volunteers (n = 33-34) in a crossover study design. A high-fat meal increased viramidine plasma AUC(0-168 h) by 44% and C(max) by 20%. It also increased ribavirin plasma AUC(0-168 h) by 19% and C(max) by 43%. The clinical relevance of these increases is unknown.     

Pharmacokinetics of GW433908, a prodrug of amprenavir,in healthy male volunteers

These two Phase I, open-label, single-dose, randomized, crossoverstudies in 40 healthymale subjects investigated the pharmacokinetic and safety profiles of various formulations of the amprenavir prodrug GW433908 in the presence and absence of food compared with amprenavir capsules. GW433908 is a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, with improved solubility over the parent molecule and a potential for reduced pill burden on current dosing regimens. The calcium salt of the prodrug, GW433908G, was selected for further investigation, as it appeared to offer the greatest potential for the development of new drug formulations. In the fasting state, (1) GW433908G tablet and suspension were bioequivalent in terms of both AUC and Cmax, and (2) GW433908G tablet and suspension were bioequivalent to amprenavir capsules for AUC; however, Cmax was lower with GW433908G. After a high-fat meal compared with fasting, (1) the bioavailability of GW433908G suspension was decreased by 20% and Cmax by 41%, and (2) for GW433908G tablets, there was no influence on AUC(12% lower Cmax). After a low-fat meal compared with fasting, (1) there was bioequivalence for GW433908G tablets, but (2) bioavailability was decreased by 23% for amprenavir capsules (Cmax was also lower, by 46%). Overall, for GW433908G and amprenavir capsules, food had a negligible influence on plasma concentration at 12 hours postdose (C12). Whether administered as tablets or suspension, GW433908G pharmacokinetics was only slightly affected by food. GW433908G tablets were well tolerated and delivered plasma amprenavir concentrations equivalent to the recommended therapeutic amprenavir dose but with fewer tablets. The possibility of a lower pill burden offered by GW433908 may be of clinical benefit in the treatment of HIV infection.     

Pharmacokinetics of tranexamic acid after intravenous administration to normal volunteers

Summary The pharmacokinetics of tranexamic acid has been investigated in two healthy volunteers. The behaviour of the drug can be described in terms of a two compartment open model; the disposition (biological) half-life was 2.7 h and 1.9 h, respectively. In five normal volunteers the mean total recovery in urine 48 h after dosing was 94.8%. The renal clearance in the two subjects, adjusted to 1.73 m² body surface area, was 135 and 132 ml/min/1.73 m², respectively, indicating that tranexamic acid is eliminated by glomerular filtration and that neither tubular excretion nor absorption takes place.     

Absorption of polar drugs following caecal instillation in healthy volunteers

We have investigated colonic drug absorption in man by the caecal instillation of a multi-component solution of atenolol, cimetidine, frusemide, hydrochlorothiazide and salicylic acid. We found that salicylic acid absorption from this solution was delayed but complete whereas the absorption of atenolol, cimetidine, frusemide and hydrochlorothiazide was four- to five-fold lower than expected from oral bioavailability studies.     

高效液相色谱法测定氨甲环酸乳膏中氨甲环酸的含量

目的建立HPL C法测定氨甲环酸乳膏中氨甲环酸的含量。方法供试品溶液制备条件采用正交试验优化。含量测定色谱条件采用Diamonsil C18色谱柱(250 mm×4.6 mm,5μm);流动相0.23%十二烷基硫酸钠溶液-甲醇(60∶40,v/v);检测波长220 nm;流速0.8 mL·min-1;柱温30℃;进样量20μL。结果提取溶剂为水-甲醇溶液(5∶5,v/v),80℃水浴搅拌加热4 min,冷却后定容,冰浴1.5 h,0.22μm微孔滤膜滤过。乳膏基质不影响氨甲环酸乳膏的含量测定。氨甲环酸在0.500 5⁴.040 mg·mL-1峰面积与浓度呈良好线性关系,r=0.999 0;最低检测限为0.49μg;最低定量限为1.64μg;平均回收率均>99%,RSD均<1.5%(n=3)。结论该方法准确、简便,专属性强,重现性好,可作为该制剂的质量控制方法。     

Pharmacokinetics of tranexamic acid in patients with ulcerative colitis and in healthy volunteers after the single instillation of 2 g rectally.

Topically applied antifibrinolytic drugs may be of value in the control of bleeding in active ulcerative colitis. Any impairment of systemic fibrinolysis in this condition, however, is potentially harmful. Since pharmacokinetic data after the rectal administration of tranexamic acid are non-existent, plasma concentration and recovery in the urine were recorded after a single dose of 2 g tranexamic acid given rectally to five patients with ulcerative colitis and to five healthy volunteers. The median area under the curve was, for the volunteers, 7.64 mg/L x hr (range: 4.43-11.56) and, for the patients, 13.84 mg/L x hr (range: 9.32-50.22) (P less than .05). The median 24-hour recovery in the urine was 0.8% (0.3-1.1) and 2.7% (1.1-4.0), respectively (P less than .05). The median peak plasma concentration was, for the volunteers, 0.40 mg/L (range: 0.20-0.69) 6 hours after administration and, for the patients, 1.10 mg/L (range: 0.53-2.90) 5 hours after administration (P less than .05). The plasma concentrations and recovery in the urine that were observed in the patients and volunteers were low compared with those seen after oral intake of the same dose. The plasma concentrations did not reach levels that were considered liable to impair systemic fibrinolysis.     

Absorption and disposition of furosemide in healthy volunteers, measured with a metabolite-specific assay

The objectives of this study were to qualitatively and quantitatively compare the metabolism, pharmacokinetics, and bioavailability of furosemide in healthy volunteers after intravenous and oral administration. We also determined the plasma protein binding of furosemide in vivo after iv administration. Nine males received furosemide (Hoechst, 40 mg iv and 80 mg po) in a random crossover fashion. Serial plasma samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced throughout the study. Furosemide as well as its potential metabolites were measured by a rapid, sensitive, and specific spectrofluorimetric HPLC assay. Total plasma clearance averaged 164 +/- 26 (SD) ml/min, of which 66.2 +/- 6.8% represented renal clearance of unchanged drug. Volume of distribution (steady-state) was 109 +/- 19 ml/kg. These clearance and volume measurements are in good agreement with data previously published by our group. The mean absolute bioavailability of furosemide was 42.8 and 44.0%, as calculated from plasma and urine data, respectively. Protein binding of furosemide in vivo was determined by a spectrofluorimetric HPLC assay and ranged from 98.5 to 99.1%. Approximately 5.5 mg of furosemide was excreted as a glucuronide conjugate after iv dosing and about 5.1 mg after po administration. We found no evidence of the proposed metabolite of furosemide, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA) in any of our plasma or urine samples. In addition, we conclusively demonstrated CSA to be an analytical artifact.     

Absorption and disposition kinetics of flunoxaprofen and benoxaprofen in healthy volunteers

Flunoxaprofen is a new nonsteroidal antiinflammatory agent that, like benoxaprofen, inhibits leukotriene rather than prostaglandin synthesis. The absorption and disposition kinetics of flunoxaprofen and benoxaprofen have been compared in six healthy volunteers after oral administration of 100 mg of each drug. The two drugs showed similar absorption characteristics, whereas the distribution and elimination processes were much faster for flunoxaprofen. The renal route of elimination appeared to contribute significantly less to the disposition of flunoxaprofen. These kinetic characteristics render less likely the risk of excessive drug accumulation with flunoxaprofen, especially in the presence of reduced renal function.     

Determination of a prodrug of tranexamic acid in whole blood by reversed-phase liquid chromatography after pre-column derivatization with fluorescamine

A sensitive high-performance liquid chromatographic (HPLC) method for a prodrug of tranexamic acid (KABI 2161) in whole blood is described. Since KABI 2161 is rapidly hydrolysed in whole blood the samples are collected directly into the extraction tubes and extracted immediately. After pre-column derivatization with fluorescamine the derivatives are analysed by reversed-phase liquid chromatography on a C(8)-Nucleosil column using an eluent mixture of phosphate buffer and acetonitrile (pH 3). The eluent is monitored by a fluorescence detector. Determinations as low as 10 ng ml(-1) of KABI 2161 in whole blood can be made when 0.5 ml blood is analysed. The precision of the method is 4.1% (RSD) at the 300 ng ml(-1) level and 6.9% (RSD) at the 50 ng ml(-1) level.     

Pharmacokinetics of the active metabolite of the prodrug repirinast in healthy Caucasian volunteers after a single oral dose

Summary The pharmacokinetics of BAY w 8199, the active metabolite of the prodrug repirinast (BAY u 2372), has been investigated after oral administration of 150, 300 and 450 mg repirinast to twelve healthy male Caucasians.Plasma BAY w 8199 concentrations were very variable between subjects. The mean peak level (geom. mean; 1s-range) was 0.14 (0.08–0.25), 0.19 (0.13–0.29) and 0.24 (0.14–0.42) mg/l after the 150, 300 and 450 mg doses, respectively. Peak levels were reached 0.5–2.5 h after drug intake. Terminal half-lives were calculated as 5.9 h (150 mg), 8.0 h (300 mg) and 9.8 h (450 mg).The dose proportionality of the plasma profiles of BAY w 8199 and of its excretion in urine was demonstrated by testing several parameters.About 7.4% of each dose (calculated as BAY w 8199) was excreted in urine over 36 h. The renal clearance of about 27 l/h suggests that BAY w 8199 is excreted by tubular secretion in addition to glomerular filtration.Abbreviations C_max maximum plasma concentration - C_max,norm dose and body weight normalized; C_max - C'(n) concentration calculated for time t_n from a log-linear regression line - t_max time of the maximum plasma concentration - AUC area under the curve from t=0 to infinity - AUC(0–12) area under the curve from t=0 to t=12 hours - AUC(0–t_n) area under the curve from t=0 to the last data point - AUC(t_n–) area under the curve extrapolated from t_n to infinity - AUC_norm dose and body weight normalized AUC-values - t_1/Z terminal half-life - Ae amount excreted into urine - CL_R renal clearance     

HPLC法测定氨甲环酸胶囊中氨甲环酸的含量

目的 建立用于测定氨甲环酸胶囊中氨甲环酸含量的HPLC法.方法 采用Karomasil-C18ODS(250mm×4.6mm,5μm)色谱柱.流动相为磷酸盐缓冲液(pH值为2.5)-甲醇(60∶30,V/V);检测波长:220 nm,流速∶1.0 mL·min-1.结果 线性范围0.4～2.0 g·L-1,r=0.9994.回收率为100.7%,RSD=0.64%(n=6).结论 本方法简便,精确,重现性好,可用于控制氨甲环酸胶囊中氨甲环酸的内在质量.     

烟酸缓释片在健康人体的生物等效性

目的 研究烟酸缓释片(广谱凋血脂药)在健康人体的药代动力学,并评价其生物等效性.方法 30名男性健康志愿者随机交叉单剂量口服试验制剂或参比制剂1.5 g,用高效液相色谱-串联质谱法测定血浆中烟酸浓度.结果 单剂量口服烟酸试验制剂或参比制剂1.5 g,药代动力学参数如下:AUC0-t分别为(20.05±16.29),(21.61±18.06)μg·h·mL-1;AUC0-∞分别为(20.81±16.30),(22.81±18.47)μg·h·mL-1;Cmax分别为(8.72±6.81),(9.57±8.22)μg·mL-1;tmax分别为(4.41±1.34),(4.31±1.29)h;t1/2分别为(4.00±4.90),(2.91±3.39)h,烟酸缓释片的相对生物利用度为(96.6±30.9)%.结论 受试制剂与参比制剂生物等效.     

夫西地酸干混悬剂在健康人体的相对生物利用度研究

目的研究由香港澳美制药有限公司生产的夫西地酸干混悬剂的相对生物利用度。方法采用双周期随机交叉试验设计。分别给予20名男性健康受试者试验制剂或参比制剂夫西地酸干混悬剂750 mg,采用HPLC法测定给药后不同时间的血药浓度。结果参比制剂与试验制剂的主要药物动力学参数Cmax、tmax、AUC0→48和AUC0→∞(均数±标准差)分别为:(30.91±5.24)、(30.25±5.82)μg.mL-1;(2.00±0.74)、(1.88±0.60)h;(443.0±136.3)、(435.6±105.2)μg.h.mL-1;(460.4±139.6)、(450.9±108.2)μg.h.mL-1。试验制剂对参比制剂的相对生物利用度F(以AUC0→48作为评价依据)为100%±13%(71%~125%)。结论经统计学分析,香港澳美制药有限公司生产的夫西地酸干混悬剂与丹麦利奥制药有限公司生产的夫西地酸干混悬剂参比制剂具有生物等效性。     

硫辛酸片在中国健康人体内的药动学研究

目的:研究硫辛酸片在中国健康人体内的药动学。方法:24名健康志愿者单剂量口服硫辛酸片200 mg,用HPLC-MS法测定健康受试者的血药浓度,并计算药动学参数。结果:主要的药动学参数如下:t1/2=(24.13±9.73)min,tmax(实测值)=(15.95±5.15)min,cmax=(1.54±0.29)μg/mL,k=(0.032 6±0.010 8)1/min,AUC0～t=(58.21±15.08)μg.min.mL-1,Vc/F=(126.65±56.67)L,CLs/F=(3.67±1.00)L/min,MRT0～t=(38.22±15.63)min。结论:中国健康志愿者口服硫辛酸片后的体内过程符合一级消除过程,本研究结果可以指导临床合理用药。     

Absorption of effervescent paracetamol tablets relative to ordinary paracetamol tablets in healthy volunteers

Objectives: The aim of this study was to compare the rate of absorption between ordinary paracetamol tablets and effervescent paracetamol tablets. Methods: Twenty healthy volunteers participated in an open randomised crossover study and were given a 1000-mg dose of either ordinary paracetamol tablets (2 × 500 mg Panodil tablets, SmithKline Beecham) or effervescent paracetamol tablets (2 × 500 mg Pinex Brusetablett, Alpharma AS) with a 3-week washout period in between. Blood samples were collected for 3 h. Maximum serum concentration (C_max) and the time to maximum serum concentration (t_max) were recorded and the area under the concentration versus time curve (AUC) was calculated. Results: The mean t_max was significantly shorter when paracetamol effervescent tablets were taken (27 min) rather than ordinary paracetamol tablets (45 min) (P=0.004). There was no significant difference between the mean C_max of 143 μmol/l with effervescent tablets and that of 131 μmol/l with ordinary tablets. The mean AUC_0–3 h was significantly higher with paracetamol effervescent tablets (223.8 μmol · h · l⁻¹) than with ordinary tablets (198.2 μmol · h · l⁻¹; P=0.003). After 15 min, 17 (85%) subjects in the effervescent group had a serum concentration of 70 μmol/l (lower therapeutic serum concentration) or higher relative to only 2 (10%) subjects in the ordinary tablet group (P=0.001). Conclusion: Paracetamol effervescent tablets are absorbed significantly faster than ordinary paracetamol. Thus, effervescent tablets might offer significantly faster pain relief when paracetamol is used. Received: 4 October 1999 ;/ Accepted in revised form: 15 February 2000     

脉络宁注射液中绿原酸在健康人体内的药动学

目的：研究单剂量和多剂量静脉滴注脉络宁注射液中绿原酸在健康人体内的药动学。方法：10名健康受试者单、多次剂量静脉滴注脉络宁注射液后,采用高效液相色谱．质谱联用法（LC／MS／MS）测定血浆中绿原酸浓度,DAS（1．0）软件对其药．时曲线进行拟合,并计算药动学参数。结果：绿原酸药．时曲线符合二房室模型,单、多次剂量主要药动学参数分别为Cmax：（252±66）、（262±87）μg／L;t1/2β：（1．35±0．53）、（1．37±0．27）h;V：（0．70±0．24）、（0．68±0．24）L／kg;CL：（0．37±0．10）、（0．34±0．11）L·kg^-1·h^-1;AUG0-tn：（404±110）、（455±151）μg·L^-1·h。结论：单剂量和多次静脉滴注脉络宁注射液后绿原酸主要药动学参数经统计学处理差异无统计学意义;连续多次给药后,绿原酸体内无蓄积现象,绿原酸的体内过程不受性别差异的影响。     

Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers

Summary Gamma-hydroxybutyric acid (GHB) is effective in treatment of the alcohol and opiate withdrawal syndromes. Its absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg kg^–1.The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentrations normalised to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased.These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range.The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.