The multiple-dosing pharmacokinetics of artemether,artesunate, and their metabolite dihydroartemisinin in rats

1. The present study was designed to investigate the multiple-dosing pharmacokinetics of antimalarial drugs artemether (ARM), artesunate (ARS), and their metabolite dihydroartemisinin (DHA) in rats.

2. Rats were randomized into four groups. Two groups of rats received oral doses of ARM or ARS once daily for five consecutive days. And another two groups of rats were given a single oral dose of ARM or ARS. Plasma samples were analysed for artemisinin drugs and their active metabolite DHA, using a validated liquid chromatography/tandem mass spectrometric (LC/MS/MS) method.

3. ARM and ARS could be biotransformed to metabolite DHA almost immediately after oral administration to rats. The area under the plasma concentration–time curve (AUC_0–t) of ARM after 5-day oral doses significantly decreased from 50.3 to 23.4 ng×h/mL (P?<?0.05), and oral clearance (CL/F) of ARM increased from 10.5 to 27.2?L/min/kg (P?<?0.05). The AUC_0–t of its metabolite DHA of ARM significantly decreased from 42.1 to 16.4 ng×h/mL (P?<?0.05), and its CL/F increased from 11.7 to 33.4?L/min/kg (P?<?0.05). The 5-day oral doses of ARS did not result in significant changes (P?>?0.05) in pharmacokinetic parameters of ARS, whereas its metabolite DHA exhibited lower AUC (P?=?0.05), compared with that obtained after a single oral administration.

4. The results showed ARM and its metabolite DHA exhibited time-dependent pharmacokinetic characteristics with decreased plasma drug level after five consecutive days of oral administration to rats, whereas ARS and its metabolite DHA did not show similar characteristics.

     

国产世福素胶囊的人体药代动力学及相对生物利用度研究

健康志愿者１０名，分别ｐｏ２００ｍｍ日本或国产世福素胶囊后，其体内过程符合一室模型，主要药动学参数分别为；Ｃａｘｍ为２．１７±０．３８及２．１７±０．３８ｍｇ·Ｌ－１；Ｔ为３．４５±０．３２及３．６０±０．５２ｈ；Ｔｐ为４．５８±０．５６及４．６２±０．３５ｈ；ＡＵＣ为２６．３５±４．２７及２５．８５±３．８０ｍｇ·ｈ－１．Ｌ－１。国产世福素胶囊与日本产世福素胶囊的相对生物利用度为９９％。血浆药物浓度采用微生物法测定。     

Pharmacokinetics and oral bioavailability of pyridostigmine in man

Summary The pharmacokinetics of pyridostigmine was evaluated after intravenous injection in two healthy male volunteers and after oral administration to five subjects. Plasma concentrations of pyridostigmine were determined after ion pair extraction from plasma and analysis by gas chromatography — mass spectrometry with chemical ionization, using d₆-pyridostigmine as internal standard. Degradation of pyridostigmine in vitro was compensated for by use of the deuterated internal standard and by rapid cooling and separation of plasma after blood sampling. After intravenous administration of pyridostigmine 2.5 mg the plasma elimination half-life was 1.52 h, the volume of distribution was 1.43 l/kg and the plasma clearance 0.65 l/kg × h. The pharmacokinetic constants were very similar after oral administration of pyridostigmine 120 mg; the elimination half-life was 1.78±0.24 h, the volume of distribution 1.64±0.29 l/kg and the plasma clearance was 0.66±0.22 l/kg × h. The bioavailability was calculated to be 7.6±2.4%. When pyridostigmine was taken together with food, the time to reach the peak plasma concentration was prolonged from 1.7 to 3.2 h. Bioavailability, however, was not influenced by concomitant food intake. Steady-state plasma concentrations of pyridostigmine were measured in myasthenic patients on their ordinary dose schedule of cholinesterase inhibitor drugs. More than a seven-fold difference in steady-state plasma concentration was found between patients taking approximately the same daily dose of pyridostigmine.     

辛伐他汀药物动力学及生物利用度

目的研究辛伐他汀(SV)的药物动力学,评价SV片剂和胶囊剂的生物等效性.方法采用反相高效液相色谱法测定10名志愿受试者单剂量口服40mgSV胶囊供试品与40mg标准参比制剂后血药浓度的变化.结果SV胶囊剂和片剂的AUC分别为(150.79±34.17)与(150.05±26.78)h*ng/ml,tmax分别为(2.35±0.41)与(2.45±0.28)h,cmax分别是(25.63±5.09)与(28.14±8.31)ng/ml.结论以SV胶囊供试品与标准参比制剂AUC、cmax和tmax为指标,经双单侧t检验,两者为生物等效制剂.     

Pharmacokinetics of ketorolac tromethamine in humans after intravenous,intramuscular and oral administration

Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design.The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min^–1·kg^–1) and a small tissue distribution (V_ss=0.111·kg^–1, V=0.17 l·kg^–1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (t_max = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.     

Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine

Summary The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers.According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h.Reduced NAC had a volume of distribution (V_SS) of 0.59 l·kg^–1 and a plasma clearance of 0.84 l·h^–1·kg^–1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%.Based on total NAC concentration, its volume of distribution (V_SS) was 0.47 l·kg^–1 and its plasma clearance was 0.11 l·h^–1·kg^–1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.     

阿斯咪唑片剂人体药代动力学和生物利用度的初步研究

目的观察阿斯咪唑片剂的人体药代动力学和生物利用度。方法用放射免疫法测定血浆阿斯咪唑 去甲阿斯咪唑含量 ,按交叉设计法对国产和进口阿斯咪唑片进行健康中国人体的药物代谢学比较研究 ,并求得相对生物利用度。用3P87软件处理。结果与结论阿斯咪唑的药代动力学呈二室模型。主要药代动力学参数 :国产片:Vd=5.34±1.85L;αT1/2=0.74±0.37h;βT1/2=286.10±220.11h;CL=0.052±0.031ng/ml;Tmax=1.56±1.32h;Cmax=1.04±0.10ng/ml;AUC=262.69±162.18ng/ml·h-1。进口片 :Vd=8.24±2.56L;αT1/2=1.16±0.98h;βT1/2=260.38±260.37h;CL=0.089±0.079ng/ml;Tmax=1.37±0.82h;Cmax=0.93±0.14ng/ml;AUC=250.66±148.05ng/ml·h -1。国产片对进口片的相对生物利用度为127.8 %。     

萘普生肠溶胶囊人体药物动力学和相对生物利用度

目的：测血药浓度，３Ｐ８７药动学程序进行药物动力学参数模拟，双单侧检验法作生物等效性判别。方法：８名健康男性志愿者交叉服用萘普生肠溶和胃溶胶囊各５００ｍｇ，以ＨＰＬＣ法测定。结果：药－时曲线符合一级吸收二室模型，萘普生肠溶胶囊的主要药动学参数分别为Ｋａ０．７５±０．２８ｈ－１，ＡＵＣ１５３３．０±２１７．６μｇ·ｈ·ｍｌ－１，Ｔｍａｘ３．６±１．６ｈ，Ｃｍａｘ７８．１±１４．１μｇ·ｍｌ－１。结论：胃溶胶囊的药动学参数与肠溶胶囊的药动学参数相似，肠溶胶囊的相对生物利用度为１０４．０１％。     

吲哚美辛缓释胶囊人体药物动力学与生物利用度

目的：研究吲哚美辛（Ｉｎｄ）缓释胶囊在正常人体内的药物动力学和相对生物利用度。方法：采用ＲＰ－ＨＰＬＣ测定Ｉｎｄ的血药浓度，研究１８名健康志愿受试者单剂量ｐｏ１５０ｍｇ国产与进口Ｉｎｇ缓释胶囊的后的人体内药物动力学和相对生物利用度。结果：两种制剂的ｔｍａｘ、Ｃｍａｘ和ＡＵＣ０→∞均无显著差异（Ｐ〉．０５）；国产Ｉｎｄ缓释胶囊的相对生物利用度为１０３．０２％。结论：两种制剂为生物等效。     

Grapefruit juice increases the bioavailability of artemether

Objective: To evaluate the effect of grapefruit juice on the pharmacokinetics of artemether in plasma and saliva after a single oral dose and to detect concentration-dependent electrocardiographic changes (bradycardia and QT_c prolongation). Methods: Six healthy male subjects were given a standard breakfast followed by two tablets of 50-mg artemether administered with water; 1 week later, the tablets were administered with 350 ml double-strength fresh frozen grapefruit juice. For 8 h, 17 blood- and saliva samples were collected, and 17 electrocardiograms were recorded. Drug and metabolite concentrations were measured by means of high-performance liquid chromatography with electrochemical detection. The pharmacokinetic parameters were determined using a one-compartment model. Results: Grapefruit juice significantly (P = 0.001) increased the mean peak concentration (C_max) of artemether more then twofold from 42 (SD 17) ng/ml to 107 (28) ng/ml. The time to reach C_max (t_max) with grapefruit juice was 2.1 (0.6) h compared with 3.6 (17) h with water (P = 0.02). The area under the concentration–time curve (AUC) almost doubled with grapefruit juice from 177 ng · h/ml to 336 ng.h/ml (P = 0.003). The elimination half-life remained unchanged (1.0 h vs 1.3 h). No major changes in the kinetics of the metabolite dihydroartemisinin were detected. Low artemether levels and zero dihydroartemisinin levels were found in saliva. No influences of artemether were observed on 17 electrocardiograms during the 8 h after drug intake – in particular there were no signs of bradycardia or QT_c prolongation. Conclusion: Grapefruit juice significantly increases the oral bioavailability of artemether without an effect on the elimination half-life. It suggests a role for intestinal CYP3A4 in the presystemic metabolism of artemether. Received: 21 December 1998 / Accepted in revised form: 15 March 1999     

Pharmacokinetics,bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate

The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F‐ara‐AMP) were evaluated in adult patients with B‐cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25 mg/m², n=14) or oral (40 mg/m², n=42) 2F‐ara‐AMP. Plasma concentrations of drug and metabolites and digital 12‐lead ECGs were monitored for 23 h after dosing. The dephosphorylated product fludarabine (2F‐ara‐A) was the principal metabolite present in the systemic circulation. Mean (±SD) elimination half‐life did not differ significantly between IV and oral dosage groups (11.3±4.0 vs 9.7±2.0 h, p=0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F‐ara‐Hx. Estimated mean oral bioavailability of 2F‐ara‐A was 58%. Compared to the time‐matched drug‐free baseline Fridericia correction of the QT interval (QTcF), the mean QTcF change following 2F‐ara‐AMP did not differ from zero, and a treatment effect of >+10 and >+15 ms could be excluded following oral and IV 2F‐ara‐AMP, respectively. Similarly, heart rate, PR interval and QRS duration did not change following 2F‐ara‐AMP treatment. Thus the 25 mg/m² IV and 40 mg/m² oral doses of 2F‐ara‐AMP produce similar systemic exposure, and do not prolong QTcF, indicating low risk of drug induced Torsades de Pointes. Copyright © 2009 John Wiley & Sons, Ltd.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.     

罗红霉素颗粒剂的药物动力学与相对生物利用度

目的:对罗红霉素颗粒剂的药物动力学与相对生物利用度进行研究.方法:采用微生物法测定8名志愿者单剂量po 300mg罗红霉素颗粒剂与片剂的血药浓度,计算两者的药物动力学参数与相对生物利用度.结果:两者药-时曲线以一级吸收双室模型拟合较好,两者的c—分别为(6.64土0·80)与(6.44土0·89)μg/ml;t_(max)_分别为(1.60土0.45)与(2.00土0.34)h;T_1/2分别为(14. 78士0.99)与(14.00士1.60)h;AUC_o_oo～分别为(100.03士18.40)与(99.01士19.21)μg·h/ml,统计学处理表明两者无显著性差异(P>0.05).结论:罗红霉素颗粒剂与片剂为生物等效制剂,罗红霉素颗粒剂的相对生物利用度为101·56%.     

赖氨匹林胶囊药物动力学与相对生物利用度

目的:研究单剂量po赖氨匹林(LA)胶囊和来比林散(LA散)后,水杨酸在血浆中的药物动力学与相对生物利用度.方法:采用反相高效液相色谱法测定10名志愿受试者单剂量po1000mg LA胶囊和4000mgLA散后,血浆中水杨酸浓度变化情况;计算药物动力学参数与相对生物利用度,并以配对t检验与双单侧t检验进行统计分析.结果:LA胶囊和LA散以水杨酸计的AUC分别是(251.81±33.58)和(255.12±44.76)mg·h/L;达峰时间分别是(3.52±0.50)和(0.97±0.4)h,峰浓度分别是(39.69±3.58)和(48.14±3.99)mg/L.配对t检验与双单侧t检验结果均表明:po1000mg LA胶囊后,以水杨酸计药-时曲线下面积与po 4000mg LA散相比无显著性差异(P>0.05);峰浓度、达峰时间以水杨酸计有显著性差异(P<0.05).结论:以AUC_(0-∝)为指标,LA囊和LA散为生物等效制剂.以LA散为标准参比制剂,LA胶囊以水杨酸计的相对生物利用度为(99.97±9.84)%.但两种制剂的t_(max)与C_(max)差异提示临床应用时应予注意.     

Pharmacokinetics and relative bioavailability of cyclobarbital calcium in man after oral administration

Summary The pharmacokinetics and relative bioavailability of cyclobarbital calcium have been studied after oral administration of Phanodorm, of tablets according to the Formularium Nederlandse Apothekers (1968; FNA), and an aqueous solution. Six healthy volunteers participated in the investigation on three occasions and each received the three preparations. The dose administered was 300 mg cyclobarbital calcium. Plasma concentrations of cyclobarbital were determined at regular intervals. Absorption from the three preparations was rapid and was faster from the solution. Peak concentrations were usually attained within 1 h. The elimination of cyclobarbital could be described by a single first-order process with an average half-life of 11.6 h (range 8 – 17 h). There was little intra-subject variation of the half-life. Relative bioavailability for each volunteer was estimated by comparing the areas under the plasma concentration curves. The FNA-tablets and Phanodorm exhibited similar bioavailability, whereas the average bioavailability of the solution was 78% of that of FNA-tablets; the reason for this unexpected finding is unknown. It was concluded that cyclobarbital cannot be regarded as a uniformly suitable drug for the treatment of insomnia. The long half-life that was apparent in some of the volunteers (15 – 17 h) creates a substantial risk of residual effects on the following morning. In principle, however, the calcium salt of cyclobarbital may be used for induction of sleep, because of its rapid absorption.     

青霉素V钾胶囊与片剂的药物动力学及相对生物利用度比较

目的比较青霉素V钾胶囊与片剂的药物动力学及相对生物利用度.方法以微生物法测定10名健康受试者单次空腹po青霉素V钾胶囊和片剂500mg后血、尿药浓度.结果po青霉素V钾胶囊和片剂后的体内过程符合二室模型.其平均cniax分别为(8.22±1.21)和(7.71±1.09)mg/L,tniax为(0.55±0.11)和(0.58±0.17)h,T1/2ka为(0.21±0.09)和(0.20±0.06)h,T1/2β为(0.81±0.21)和(0.72±0.08)h,AUC为(9.51±1.06)和(9.50±1.82)h@mg/L,24h累积尿排出率分别为给药量的(35.33±7.45)%和(37.80±5.45)%.青霉素V钾胶囊与片剂的药物动力学参数间差异无统计学意义(P＞0.05).结论青霉素V钾胶囊的相对生物利用度为(101.44士9.59)%,与片剂具生物等效性.