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.     

Pharmacokinetics of fluoride in man after single and multiple oral doses

Summary The doses of fluoride (F) recommended in the literature for caries prevention and for the treatment of osteoporosis vary. This partly reflects inadequate knowledge of F pharmacokinetics. In the present study various single and multiple oral doses of F were given to eight volunteers, who had a strictly controlled F intake in the diet. The resulting plasma and parotid saliva concentrations as well as urinary output of F were measured. The plasma data fitted a two-compartment open model with a -slope half-life ranging between 2 and 9 h. Plasma clearance was 0.15±0.02 (SD) liter/kg/h. Data from the highest dose (10 mg) were fitted to both two- and three-compartment models, and there was no significant difference between them. Multiple doses of F 3.0 or 4.5 mg yielded steady state concentrations ranging from 54 to 145 ng/ml. About 50 per cent of the given dose was recovered in the urine, which is indicative of considerable accumulation in the body. The saliva F/plasma F concentration ratio was 0.64 with a coefficient of variation of 5%.     

Pharmacokinetics of single and multiple doses of phenytoin in man

Summary Plasma concentration of phenytoin (diphenylhydantoin, DPH) have been studied in 5 volunteers after single oral and iv doses (5.0 mg sodium DPH/kg), and after multiple oral doses (2.0 mg sodium DPH/kg b.i.d. for 12 days). The data were analysed according to a one compartment model. The plasma half-life was 14.5 h±1.2 S.D. after i.v. administration, its apparent volume of distribution varied little (0.52 l/kg±0.04) and its bioavailability ranged between 0.70 and 1.0 (mean 0.87). After oral administration peak plasma concentrations were reached in 4 to 12 h. Elimination curves were slightly convex, probably due to an effect of slow absorption. Steady-state plasma levels varied twofold between individuals after multiple oral doses and exceeded those predicted from the single i.v. dose by 29 to 77%. The discrepancy was considered to be due to transition to dose-dependent kinetics.This is the last paper written in collaboration with Dr. Balzar Alexanderson before his untimely death on 2nd June 1973. We are grateful for the inspiring and fruitful experience of working with him. To honour his memory as a good friend and brilliant clinical pharmacologist a number of papers from our laboratory will be dedicated to him.     

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.     

Pharmacokinetics of ketoprofen following single oral,intramuscular and rectal doses and after repeated oral administration

Summary The pharmacokinetics of ketoprofen was studied in the same healthy subjects after single oral, intramuscular and rectal doses, and after repeated oral administration. No significant difference in the mean t_1/2 (1.13–1.27 h) was observed after the different modes of administration. The mean [AUC] ₀ after rectal administration of a suppository showed the minimum significant difference (p<0.05) from that after oral administration of the capsule. The apparent volume of distribution (Vd/F) was approximately 10–15% of body weight. The renal contribution (mean, 0.10–0.15 ml/min/kg) to the plasma clearance of free ketoprofen was assumed to be, at most, 8.3–12.9%. The projected cumulative excretion of total (free plus conjugated) ketoprofen via urine exceeded 63–75% of the dose, of which approximately 90% was ketoprofen glucuronide. A mean of 71–96% and 73–93% of the oral capsule was estimated to be systemically available after administration of the intramuscular preparation and rectal suppository, respectively. In four of seven subjects, CPK concentration was elevated after the intramuscular injection. The mean steady-state concentration of ketoprofen in plasma ranged from 0.43 to 5.62 µg/ml after the final dose of a 50 mg q.i.d. regimen. The disposition data and plasma levels observed at steady-state were in agreement with those predicted from the single oral dose study. The accumulation ratio was 1.08±0.08. The results suggest that the rectal suppository can be recommended as an extravascular mode of administration of this drug.A preliminary account of this work was presented at the 10th Congress of Japanese Society of Clinical Pharmacology, Sapporo, 27 August 1979     

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%.     

国产格列本脲和二甲双胍复方制剂在健康志愿者的药动学和相对生物利用度

目的:比较国产格列本脲和二甲双胍复方制剂在健康志愿者的药动学和相对生物利用度。方法:20例受试者随机交叉单剂量口服国产格列本脲和二甲双胍复方制剂(盐酸二甲双胍:格列本脲=500 mg:5 mg,简称试验制剂)与格列本脲片和盐酸二甲双胍片2个相同剂量单药(简称参比制剂),用液相色谱-质谱法和高效液相色谱法测定血清中格列本脲和二甲双胍的浓度。结果:试验与参比制剂中格列本脲的药动学参数分别为:AUC0-t为(1 184．8±369．4)和(1 110．5±437.2)μg·h·L-1,Cmax为(211．8±57．8)和(176．7±46．0)μg·L-1,Tmax为(3．38±0．94)和(3．43±1．03)h;2种制剂中二甲双胍药动学参数分别为:AUC0-t为(7 219．8±1 964．6)和(7 376．8±2 060．2)μg·h·L-1,Cmax为(924．7±206．2)和(1 01 1．9±331．7)μg·L-1,Tmax为(3．60±1．20)和(3．55±1．09)h。试验制剂中格列本脲和二甲双胍的相对生物利用度分别为(109．5±17．0)％和(105．2±33．4)％。结论:国产格列本脲和二甲双胍复方制剂与组成复方的2个相同剂量单药的药动学比较显示相同的相对生物利用度。     

尼莫地平漂浮缓释片的人体药物动力学及相对生物利用度

目的:比较尼莫地平(Nim)漂浮缓释片与普通片的药物动力学、相对生物利用度及体内外相关性.方法:10例男性健康受试者自身交叉对照、单剂量po Nim漂浮缓释片或普通片各120mg,采用HPLC法测定血浆Nim浓度,单室模型拟合药物动力学参数.结果:Nim缓释片和普通片的t_(max)分别为(2.83±0.45)和(0.87±0.27)h(P<0.01),C_(max)分别为(32.82±6.36)和(48.71±8.94)ng/ml(P<0.01),AUC分别为(204.81±45.03)和(159.98±39.96)h·ng/ml(P<0.01).数据经对数转换后进行双单侧检验,两种制剂生物不等效;缓释片的相对生物利用度为(129.89±17.02)%;其体内吸收与体外释药具有显著的相关性(P<0.01).结论:Nim漂浮缓释片生物利用度优于普通片,达到剂型设计要求.     

Pharmacokinetics of oral glycerol-1-nitrate

Summary The plasma kinetics and urinary excretion of glycerol-1-nitrate (G-1-N), a water soluble metabolite of glycerol trinitrate with anti-anginal potential, have been investigated in healthy human volunteers following oral doses of 10, 20 and 40 mg tablets and 20 mg as drops. In all volunteers G-1-N was rapidly absorbed. The mean concentration-time curves peaked 40 min after administration of tablets at 144 ng/ml (10 mg), 308 ng/ml (20 mg) and 573 ng/ml (40 mg). After the drops the peak of 324 ng/ml occurred at 1 h. The areas under the G-1-N concentration-time curve and the G-1-N peak heights were linear with dose. Tablets and drops can be regarded as bioequivalent with respect to area under the curve and elimination half-life. The bioavailability of the 20 mg tablet relative to the 20 mg drops was 98.6% in terms of area under the curve. The mean apparent half-life of G-1-N elimination from plasma was 2.69±0.67 h (n=46). The mean residence time of G-1-N in the body was 4.65 h compared to 0.28 h for glycerol trinitrate after buccal administration. Female volunteers were found to have significantly lower areas under the curve than male volunteers. The difference was probably due to differences in body weight. Renal excretion does not play an important role in the elimination of oral G-1-N from the body. An overall average of 5.42% of the G-1-N dose was excreted in the urine; free drug accounted for 4.02% and conjugated drug for 1.40%.     

Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac hioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.The present work is part of a research project developed with a grant for the Plan Nacional de I + D (FAR 90-0092) of the Ministry of Industry and Energy of Spain.     

地高辛口服液在健康人体的药代动力学和相对生物利用度

目的研究地高辛口服溶液与片剂在健康人体的药代动力学和相对生物利用度。方法20名健康受试者随机交叉、单剂量口服地高辛口服溶液和片剂;用偏振荧光免疫法测定血清中地高辛浓度,计算2种制剂的药代动力学参数,并进行生物等效性评价。结果地高辛口服液和片剂的药代动力学参数AUC0→∞分别为(65.19±12.09)和(67.59±9.77)μg·h·L-1,AUC0→72分别为(42.04±6.25)和(44.91±6.03)μg·h·L-1,tmax分别为(0.64±0.17)和(1.36±0.79)h,Cmax分别为(3.99±1.23)和(3.53±1.02)μg.L-1,t1/2分别为(44.66±8.12)和(44.67±5.02)h。2种制剂(tmax外)均无显著性差异(P>0.05);地高辛口服液的相对生物利用度为(94.8±16.4)%。结论2种制剂具有生物等效性。     

盐酸曲马多分散片人体药物动力学及相对生物利用度

目的 研究国产盐酸曲马多分散片的人体药代动力学参数和生物等效性.方法 12名健康受试者交叉口服国产盐酸曲马多分散片100mg和进口盐酸曲马多胶囊100mg,用HPLC法测定血浆中药物浓度.结果 两种制剂的血药浓度曲线均符合二室模型,T_(1/2)分别为(7.69±3.74)h和(7.66±3.41)h,血药浓度曲线下面积分别为(3100±1165)μg·h·L~(-1)和(3212±1260)μg·h·L~(-1),两种制剂的药代动力学参数均无显著性差异(P>0.05).结论 两种制剂的口服生物利用度具有生物等效性.     

Pharmacokinetics and relative bioavailability of selegiline in healthy volunteers

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. A sensitive fluorimetric assay based on ibhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to study the pharmacokinetics of selegiline. This method quantitates selegiline as low as 0.25 ng ml^?1. The pharmacokinetics and relative bioavailability of selegiline were investigated in healthy volunteers following oral administration of 10 mg tablet or solution. A half-life of approximately 70 min was observed following the administration of either dosage form. Although the two dosage forms exhibited a lag time, the absorption was rapid and peak plasma concentrations were observed between 30 and 45 min for the solution and 30 and 90 min for the tablets. Statistically no significant difference was found between C_max, T_max, AUC_0-∞ and MRT between the two dosage forms. Negligible renal clearance was found in both groups, but aparent oral plasma clearance was comparatively high and indicates rapid elimination of selegiline from the body.     

复方磺胺甲恶唑分散片在正常人体内的药代动力学及相对生物利用度

本文采用HPLC法同时测定血浆中复方磺胺甲噁唑吐分散片中SMZ和TMP的浓度,采用HypersilODS柱,流动相为乙腈:醋酸钠(pH6.4 0.lmol/L)=22:78(V/V),检测波长230nm,流速为1.00ml/min.10名志愿受试者自身交叉口服Go-SMZ片和Co-SMZ分散片800mg,结果显示SMZ和TMP的Cmax分别为46.69±7.66μg/ml,44.61±6.37μg/ml和1.82±0.49μg/ml,1.63±0.43μg/ml;Tmax为3.41±1.59h,3.4±0.84h和1.48±0.83h,1.50±0.81h;AUC为761±l29.37μg.h/ml,761.79±145.6μg.h/ml和26.91±3.89μg.h/ml,26.96±4.7lμg.h/ml.分散片中SMZ和TMP相对于参比制剂的相对生物利用度分别为101.28±14.35%,101.26±15.76%.     

Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion

AIMS: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. RESULTS: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. CONCLUSIONS: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.     

Plasma kinetics of methaqualone in man after single oral doses

Summary Plasma concentrations of methaqualone were followed for several days after single oral doses in 5 healthy subjects. The analysis of methaqualone was performed by gas chromatography-mass spectrometry (mass fragmentography). The plasma levels of methaqualone were interpreted according to a two compartment model. The elimination rate of methaqualone was found to be much slower than has been reported previously, half lives in the -phase ranging from 19.6 to 41.5 h.     

孟鲁司特钠药动学及其国产片剂/咀嚼片剂人体相对生物利用度研究

目的:研究孟鲁司特钠在健康人体内的药动学及国产制剂的人体生物等效性。方法:采用三制剂三周期二重3×3拉丁方实验设计,24例健康男性受试者交叉口服试验制剂和参比制剂10 mg,24h时间周期内间隔采集静脉血,处理后血浆样本用HPLC测定。计算片剂和咀嚼片剂的药动学参数,并以进口片剂作对比,估算国产制剂人体相对生物利用度,评价生物等效性。结果:国产孟鲁司特钠片剂/咀嚼片制在中国健康男性受试者体内的药动学特征基本符合线性动力学一室开放模型,其AUC_(0～24h)分别为(3051．11±671．30)和(3038．37±585．03)μg·h·L~(-1);C_(max)分别由(341．01±75．11)和(342．36±75．93)μg·L~(-1);T_(max)分别为(3．52±0．31)和(3．42±0．46)h。计算得孟鲁司特钠片剂/咀嚼片剂的平均人体相对生物利用度分别为(99．95±8．22)%和(100．05±9．32)%。结论:孟鲁司特钠国产制剂与进口片剂具生物等效性。     

盐酸格拉司琼胶囊的人体药物动力学和相对生物利用度

目的 :研究盐酸格拉司琼胶囊在健康人体内的药物动力学和相对生物利用度。方法 :12名健康男性志愿受试者单剂量口服盐酸格拉司琼胶囊或市售片 12 mg后 ,采用高效液相色谱法测定血浆中格拉司琼浓度。结果 :经 3P87药物动力学程序处理 ,以格拉司琼胶囊和片剂的 AUC0→ t分别为 (133.7± 6 1.8)、(131.1± 5 7.4) ng· h/m l;AUC0→∞ 分别为 (15 0 .9± 6 9.8)、(15 0 .6± 6 7.5 ) ng· h/m l,tmax分别为 (2 .9± 0 .4)、(2 .9± 0 .3) h,cmax分别为 (2 4.6± 9.3)、(2 4.6± 8.7) ng/ml。经配对 t检验两种盐酸格拉司琼制剂的 AU C及 cmax无显著性差异 (P>0 .0 5 )。以盐酸格拉司琼片为标准参比制剂 ,盐酸格拉司琼胶囊的相对生物利用度为 F0→ t(10 1.5± 11.2 ) % ;F0→∞ (10 0 .2± 13.5 ) %。结论 :盐酸格拉司琼胶囊和片剂为生物等效制剂。     

缬沙坦胶囊在人体的药物动力学及相对生物利用度

目的 :了解国产缬沙坦胶囊在人体的药物动力学和相对生物利用度。方法 :采用随机交叉试验设计 ,2 0名男性健康志愿者单剂量口服试验品与参比品各 80mg ,用HPLC法测定血药浓度。结果 :试验品与参比品主要药物动力学参数为T1/ 2α:(1 86± 0 93)h与 (1 94± 0 80 )h ,T1/ 2 β:(9 93± 3 41)h与 (9 81± 4 18)h ,tmax:(2 33± 0 80 )h与 (2 2 8± 0 47)h ;cmax:(2 6 1±1 15 ) μg·mL-1与 (2 43± 1 0 4) μg·mL-1,AUC0→T:(17 2 5± 6 90 ) μg·h·mL-1与 (16 92± 6 34 ) μg·h·mL-1。经交叉试验方差分析 ,上述药物动力学参数无统计学差异 (P >0 0 5 )。试验品的相对生物利用度为 (10 2 2 7± 14 2 6 ) %。结论 :试验品与参比品的cmax与AUC0→t经双单侧t检验分析 ,结果表明两者具有生物等效性。     

国产和进口盐酸格拉司琼片人体药物动力学和相对生物利用度

目的比较国产和进口盐酸格拉司琼片(Gra)的药物动力学和生物利用度.方法按照随机交叉试验方法研究了国产及进口Gra片在9名男性自愿者中的药物动力学和相对生物利用度.po单剂量2mg上述两种制剂,采用HPLC-荧光检测法测定给药后不同时间的血药浓度.结果国产片和进口片的tmax分别为(1.45±0.98)和(1.29±0.52)h;cmax分别为(7.23±1.94)和(6.78±2.86)ng/ml;T1/2分别为(5.33±2.65)和(5.43±2.32)h;Vd分别为(236.3±79.25)和(308.8±154.9)L;CL分别为(30.7±5.2)和(39.4±5.7)L/h;MRT分别为(6.41±2.10)和(6.73±1.75)h;AUC0→∞分别为(70.55±50.19)和(68.09±42.68)ng*h/ml.经配对t检验上述参数差异均无显著意义(P＞0.05).国产片相对于进口片的生物利用度为(102.45±16.91)%.结论2种制剂具有生物等效性.