The influence of gastrointestinal transit on drug absorption in healthy volunteers.

1. The effect of variability of gastric emptying and oro-caecal transit on the absorption of a multicomponent solution of frusemide, atenolol, hydrochlorthiazide and salicylic acid has been studied in six healthy subjects. Each subject was studied on five separate occasions: three times under basal conditions, once following metoclopramide and once following codeine pretreatment in an attempt to speed and slow transit respectively. 2. Inter-subject variability of gastric emptying, oro-caecal transit and the rate and extent of drug absorption was considerable. 3. The absorption of salicylic acid appeared rate-limited by gastric emptying but the rate and extent of frusemide, atenolol and hydrochlorthiazide absorption were unrelated to measures of gastric emptying or oro-caecal transit. 4. Codeine phosphate caused a two-fold delay in oro-caecal transit but did not influence gastric emptying while metoclopramide had no significant effect on either function. 5. Metoclopramide and codeine had no significant effect on the rate or extent of absorption of any of the study drugs. 6. Within the limits of this experiment, oro-caecal transit time did not appear to be an important determinant of frusemide, atenolol, hydrochlorothiazide or salicylic acid absorption. Other factors must account for the observed variability in drug absorption.     

The pharmacokinetics of dapsone after oral administration to healthy volunteers.

After oral administration of 100 mg dapsone (DDS) to 25 healthy volunteers peak serum DDS concentrations between 1.10 and 2.33 mg l-1 were reached within 0.5 to 4 h. AUCs varied from 20.3 to 75.4 mg l-1 h, while the elimination half-lives ranged from 11.5 to 29.2 h. The apparent volumes of distribution were 0.84 to 1.26 l kg-1 body weight, assuming complete bioavailability. Statistically significant differences in peak drug concentration, peak time and AUC existed between males and females. Absorption and elimination of DDS appeared to be faster than reported in other studies, suggesting differences in DDS kinetics between healthy volunteers and patients.     

Bioavailibility of paracetamol after oral administration to healthy volunteers

The absorption rate and the bioavailability of two commercially available paracetamol tablets were investigated in a panel of seven volunteers; one of these tablets contained a combination of 50 mg caffeine and paracetamol. Considering the urinary excretion data, it is concluded that the tablets release their contents completely; the absolute bioavailability, however, calculated from plasma concentrations, is lower than 100%, indicating a first-pass effect. A marked interindividual variation in first-pass effect was noticed. No general influence of caffeine on the extent of absorption of paracetamol could be established; there is, however, a slightly positive influence of caffeine on the absorption rate of paracetamol in six out of seven volunteers. It was concluded that this positive influence on absorption rate is not responsible for the established enhancement of paracetamol analgesia by caffeine.     

Pharmacokinetics of pramiracetam in healthy volunteers after oral administration.

The pharmacokinetics of pramiracetam was assessed using an HPLC method after oral administration of two different formulations of 600 mg (a solution and a tablet) of pramiracetam to 11 fasting volunteers. The mean kinetic parameters were: t1 = 4.7 +/- 2.4 - 4.3 +/- 2.2 h, AUC = 57.6 +/- 43.6 - 47.2 +/- 33.9 micrograms h/ml, Cmax = 6.80 +/- 3.2 - 5.80 +/- 3.3 micrograms/ml for the solution and the tablet respectively. The plasma profile of pramiracetam proved to be not highly affected by the formulation, only that the absorption rate was faster after oral administration of the drug in solution than after administration as a tablet. The half-life was very variable between subjects [2-8 hours], but less variable within subjects and it was unaffected by the formulation.     

Pharmacokinetics of mifentidine after single and multiple oral administration to healthy volunteers.

1. The pharmacokinetics of mifentidine, a new long acting histamine H2-receptor antagonist, were studied using two protocols. 2. In one study, on 5 different days six normal male subjects were given 2.5, 5, 10, or 20 mg mifentidine or placebo orally 60 min before starting a 3 h continuous gastric aspiration during which time blood samples were taken for measurement of mifentidine concentration. 3. The area under the curves of mifentidine plasma levels (AUC) vs time for the four doses was linearly related to the dose for each individual subject (r = 0.972, P less than 0.001). After doses of 2.5, 5, 10 and 20 mg, mifentidine reduced hydrogen ion output by respectively 36, 37, 60 and 75% and secretory volume by 1, 17, 40, and 47%. The effects at the two highest doses were statistically significant. AUC was correlated positively with the percentage reduction in hydrogen ion output (r = 0.802, P less than 0.001) and volume (r = 0.834, P less than 0.001) over a 3 h period. 4. In the second study, the pharmacokinetics were evaluated after once-daily treatment for 14 days in seven subjects given 10 mg and in seven others subjects given 20 mg. 5. After multiple dosing, renal clearance was similar for the two doses (11.6 +/- 2.11 l h-1 for the low dose and 17.0 +/- 2.0 l h-1 for the high dose). Plasma half-life (t1/2 lambda 2) was 16.0 +/- 3.0 h after the 10 mg dose and 11.9 +/- 1.2 h after 20 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of dimetindene after intravenous and oral administration to healthy volunteers

The pharmacokinetics of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) were studied after its intravenous and oral administration to 8 healthy male volunteers. Serum concentrations were measured for 48 h using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters (AUC, t1/2, CLs, Vd and F) were calculated using the clearance approach.     

Evaluation of gastrointestinal transit characteristics of oral patch preparation using caffeine as a model drug in human volunteers

Salivary caffeine excretion rate test has been proposed for the evaluation of gastrointestinal transit characteristics of an oral patch preparation after administration to human volunteers instead of measuring the plasma or serum concentration in the early stages of formulation development. Patches having a diameter of 3.0 mm and containing caffeine as a model drug were prepared. The patches consisted of 1) the backing layer made of a water-insoluble polymer, 2) the drug-carrying layer composed of caffeine and a gel-forming polymer, and 3) the enteric polymer membrane. These three layer patches were filled into enteric capsules. Caffeine solution in an enteric capsule was used as the control preparation. After oral administration of each preparation to human volunteers at a dose of 50 mg of caffeine in a cross-over study with a wash-out period of two weeks, saliva samples were collected over 1 min at every sampling time for 12 h and salivary caffeine concentration was determined by a HPLC assay method. Salivary caffeine excretion rate (ER) was used for pharmacokinetic analysis. Mean residence time (MRT) and first-appearance time of caffeine into the saliva (T(i)) were determined. To characterize the pharmacokinetics of caffeine, MRT-T(i) values of patch and solution preparations were compared. Patch preparations had a T(i) value of 2.33+/-0.33 h and showed significantly longer MRT-T(i), 3.87+/-0.21 h, as compared to the control preparation (MRT-T(i)=1.04+/-0.38 h) under fasting condition (p<0.05). Food intake prolonged the gastric emptying time (GET) of the preparations with T(i) values of 5.00+/-1.15 h for control preparation and 4.67+/-1.20 h for patch preparation. The MRT-T(i) values were 0.62+/-0.20 h (control) and 2.45+/-0.73 h (patch). The results of this study indicate that the parameter, MRT-T(i), was useful in characterizing the transit characteristics of oral patch preparations than MRT itself and the presence of food affects the performance of the patch system.     

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-blocking agent, in the plasma and urine of 12 healthy volunteers were investigated after intravenous (iv) and oral (two formulations) administration. The study was conducted with an open, randomized Latin squares design. Plasma and urine levels of moxisylyte and its biotransformation products were assayed by a specific HPLC method with fluorescence detection. Plasma levels declined in a monophasic or biphasic pattern depending on the subject. Two metabolites, conjugated desacetylmoxisylyte (DAM) and conjugated monodesmethylated DAM (MDAM), were found in plasma and urine. Unconjugated DAM was found in plasma only after iv administration. The apparent elimination half-lives of unconjugated DAM, conjugated DAM, and MDAM were 0.86, 1.7, and 3 h, respectively. The total amounts of metabolites (expressed as the equivalent of DAM) excreted in the urine were 75% after i.v. administration and 68 and 69% after oral administration of the two formulations. Oral absorption appeared to be complete for the two treatments. There was no statistical difference between the two oral formulations studied.     

Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers

Summary The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.     

Comparative bioavailability of two cefdinir suspension formulations in Middle Eastern healthy volunteers after single oral administration

The aim of this study was to compare the bioavailability, after oral administration, of the generic "Adcef Suspension" (test) (125 mg/5 ml cefdinir; CAS 91832-40-5), with that of a commercially available original preparation (reference) (125 mg/ 5 ml cefdinir). For this purpose a randomized, two-way, crossover, bioequivalence study was performed in 24 healthy, male volunteers. The Middle Eastern selected volunteers were divided into two groups of 12 subjects. One group was treated with the reference standard and the other one with the test, with a crossover after the drug washout period of 7 days. Blood samples were collected at fixed time intervals and cefdinir concentrations were determined by a validated HPLC assay method. The pharmacokinetic parameters AUC(0-24), AUC(0-infinity), C(max), T(max), K(e) and T1/2 were determined for both formulations and were compared statistically to evaluate the bioequivalence betwee the two brands of cefdinir, using the statistical model recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on the statistical evaluation it was concluded that the two formulations exhibit.     

Bioequivalence assessment of ambroxol tablet after a single oral dose administration to healthy male volunteers.

A bioequivalence study of the ambroxol hydrochloride tablets was conducted. Twenty-four healthy male Korean volunteers received each medicine at the ambroxol hydrochloride dose of 30 mg in a 2 x 2 cross-over study. There was a 1-week washout period between the doses. Plasma concentrations of ambroxol were monitored by a high-performance liquid chromatography (HPLC) for over a period of 24h after the administration. AUC(t) (the area under the plasma concentration-time curve from time 0 to last sampling time, 24h) was calculated by the linear-log trapezoidal rule method. C(max) (maximum plasma drug concentration) and T(max) (time to reach C(max)) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(t) and C(max), and untransformed T(max). The geometric mean of AUC(t) was 495.8 ng ml(-1)h(-1) (test medication) and 468.3 ng ml(-1)h(-1) (reference medication). C(max) of 61.5 and 57.3 ng ml(-1) were achieved for the test and the reference medication, respectively. The point estimates and 90% confidence intervals for AUC(t) (parametric) and C(max) (parametric) were, in point estimate (90% confidence interval), 1.058 (0.989-1.134) and 1.073 (1.007-1.142), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of T(max) was 0.229 (0.015-0.444). These results indicate that the two medications of ambroxol hydrochloride are bioequivalent and, thus, may be prescribed interchangeably.     

单次口服伐地那非片在健康志愿者的耐受性

目的 观察伐地那非对中国健康男性志愿者的耐受性。方法 用随机、双盲、安慰剂对照、剂量递增试验设计,48名入选者,单次口服5,10,20和40 mg伐地那非分别对比给药前后及各剂量组间受试者的临床症状和实验室化验结果。结果 服药前后,受试者的体征没有显著性变化,组间受试者的体征没有明显差异,试验室检查结果中个别指标虽有统计学意义,但均在正常范围内,无临床意义。结论 受试者对伐地那非5～40 mg的应用剂量具有很好的耐受性,临床推荐1 0～20mg单次服用剂量。     

单剂口服盐酸托烷司琼颗粒剂在健康人体的生物等效性

目的研究盐酸托烷司琼颗粒剂的药代动力学特征及生物等效性。方法用随机交叉给药方法,20名健康男性志愿者分别单剂量口服盐酸托烷司琼颗粒剂试验药及胶囊对照药20mg,用LC-MS/MS法测定血药浓度。计算2者的药代动力学参数及相对生物利用度。结果口服托烷司琼颗粒剂试验药及胶囊对照药20mg的主要药代动力学参数AUC0-t分别是:(523.82±432.96)和(547.04±455.59)ng·h·mL-1;AUC0-∞分别为(568.07±491.48)和(591.77±513.15)ng·h·mL-1;Cmax分别为(36.67±12.30)和(37.44±14.30)ng·mL-1;tmax分别为(1.85±1.66)和(1.85±0.79)h;t1/2分别为(9.76±6.33)和(9.77±5.51)h。相对生物利用度为(98.03±17.11)%。结论2种制剂具有生物等效性。     

The bioavailability and pharmacokinetics of guanfacine after oral and intravenous administration to healthy volunteers

Guanfacine is a centrally acting alpha-2 adrenergic agonist. The absolute bioavailability, pharmacokinetics, and renal clearance of this antihypertensive drug were investigated in healthy male volunteers. Eighteen subjects received a single oral or intravenous dose of guanfacine 3 mg in a two-way cross-over study design. Blood samples were obtained before dosing and up to 72 hours after dosing for determination of drug levels in plasma. Additional blood samples were obtained for protein binding studies. Urine was collected and pooled for specific intervals up to 96 hours after dosing. The absolute bioavailability of guanfacine after a single oral dose was 81.1%. The elimination half-lives were 13.8 hours and 13.4 hours after oral and intravenous administration, respectively. The volume of distribution results were approximately 6 L/kg by both routes of administration. The mean plasma protein binding results were 71.6%, not influenced by plasma concentration or route of administration. The urinary recovery of guanfacine was 44.3% after oral dosing and 50% after intravenous dosing. Renal clearance of guanfacine was 50% of total body clearance and appeared to be due to a net renal tubular secretory process.     

甲磺酸加替沙星片健康人单剂口服药代动力学

目的研究健康人口服单剂甲磺酸加替沙星片后药代动力学特征,为该药II期临床试验提供依据。方法采用3剂量3周期拉丁方实验设计。9名健康受试者单剂口服甲磺酸加替沙星片100、200、300mg,HPLC法测其血清、尿药物浓度。结果受试者口服甲磺酸加替沙星片后,人体耐受良好,体内过程符合二室开放模型。主要药代动力学参数与给药剂量呈线性关系,tmax为0.5～0.7h,Cmax分别为1.42、2.42、3.25μg/ml,AUC0-∞分别为11.33、21.85、32.32μg·h/ml,V/Fc值为50～80L,t1/2β为8～9h,72h尿药累积回收率约为63.5%。结论甲磺酸加替沙星片口服吸收良好,血峰浓度高,组织分布广,消除半衰期长。200mg每日一次口服用于治疗敏感菌感染。     

单剂口服多潘立酮片在健康人体的生物等效性

目的评价2种多潘立酮片的生物等效性。方法选择健康成年男性20名,随机分为2组,每组10人,自身前后交叉分别口服2种多潘立酮片10mg;用高效液相色谱法测定血药浓度,用3P97软件计算药代动力学参数,考察其生物等效性。结果20名健康受试者口服2种多潘立酮片的主要药代动力学参数tmax分别为(0.73±0.23),(0.73±0.24)h;Cmax分别为(18.78±4.50),(19.69±6.97)μg·L-1;AUC0-t分别为(74.84±19.61),(78.74±22.14)μg·h·L-1;相对生物利用度为95.54%。结论2种多潘立酮片具有生物等效性。     

单次口服复方尼群地平片在健康人体的耐受性

目的 评价健康志愿者单次口服复方尼群地平片（抗高血压药）的耐受性。方法 40名健康志愿者随机分为5组，每组分别单次口服复方尼群地平0．2，1，2，3，及4片。观察服药前后，各组的血压、心率、临床症状、心电图和实验室指标变化。结果 单次口服复方尼群地平片后，平均坐位收缩压和舒张压均下降（P〈0．05），降压作用1h起效，且可维持6～8h（除0．2片组）；服药后，降压幅度各组比较无显著性差异（P〉0．05）；平均坐位心率减慢（P〈0．05），以服4片组心率减慢最明显；服药后，平均坐位心率下降幅度各组比较有显著性差异（P〈0．05）；未发生体位性低血压、不能耐受药物不良反应及实验室指标异常。结论 健康志愿者对复方尼群地平片能较好耐受。     

Pharmacokinetics of alfuzosin after single oral administration to healthy volunteers, of three different doses.

The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2.5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2 beta) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1-5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2.5, and 5 mg were, respectively: tmax (h) 1.5 +/- 0.3, 1.1 +/- 0.2, 1.3 +/- 0.1; Cmax (ng ml-1) 2.6 +/- 0.3, 9.4 +/- 1.2, 13.5 +/- 1.0; AUC (ng ml-1 h) 17.7 +/- 2.9, 51.7 +/- 7.1, 99.0 +/- 14.1; t1/2 (h) 3.7 +/- 0.4, 3.9 +/- 0.2, 3.8 +/- 0.3. Cmax (corrected by the dose) obtained after 2.5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2.5 mg and 4 volunteers of 12 after 5 mg.     

健康志愿者口服单剂量阿德福韦酯片剂的耐受性试验

目的:评估健康成年中国男性接受单次口服阿德福韦酯片剂的安全性。方法:采用单中心、安慰剂对照、随机双盲,分5个剂量组(5,10,20,30和60 mg),每组服用试验药6名,安慰剂2名,共40名受试者入选, 全部为男性,年龄为(26±s 5)a,21～39 a。研究剂量从5 mg依次由低到高递增到60 mg,每组研究期5 d。安全性评估项目为生命体征,心电图,实验室检查包括血常规、尿常规、血生化、凝血功能、血清病毒学检查。评估时点为给药后24 h,给药后96 h。结果:5个剂量组共30名受试者服用了试验药物,其中发生与阿德福韦酯片剂可能相关的轻度不良事件1次。结论:中国健康成年男性单次口服阿德福韦酯片剂,最高剂量60 mg 时人体耐受性良好。     

Evaluating drug absorption after oral administration. Some problems and some solutions

Summary Quantitative assessment of drug absorption remains a difficult task, because the multiple-compartment disposition of a drug may not be obvious after oral administration (the problem of the vanishing exponential) and the macroconstants are indistinguishable. For these reasons, proper analysis of the drug absorption based on the apparent behavior of oral data without intravenous reference curve rarely provides absorption information useful for in vivo — in vitro correlations. When intravenous reference curve is available, compartment model used for analysis of the oral data should be corresponding to the iv data such as the Loo-Riegelman method. The model independent statistical moments method is one of the preferable alternatives because of its ease of computation and its potentially smaller error, if absorption can be assumed to be first-order.