Effect of congestive heart failure on the pharmacokinetics of cibenzoline

Six patients with chronic congestive heart failure (CHF) (New York Heart Association functional class II or III) and five healthy subjects completed this study designed to determine if CHF alters the pharmacokinetics and absolute bioavailability of cibenzoline when compared with healthy subjects. Each subject or patient was administered a one-hour intravenous infusion of 80 mg of 15N2-cibenzoline and simultaneously received an 80-mg oral dose of cibenzoline that allowed for analytic separation of each route of administration. Resulting plasma concentration-time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for cibenzoline. There were no statistically significant differences in any pharmacokinetic parameter between patients with CHF and healthy subjects. The absolute bioavailability ranged from 74% to 97% in those with CHF. The volume of distribution following the intravenous dose ranged from 3.4 to 6.1 L/kg, and plasma clearance ranged from 245 to 642 mL/min, with an apparent elimination half-life of approximately ten hours. Approximately 60% of the dose was recovered in the urine. Overall, the pharmacokinetics of cibenzoline in patients with chronic CHF do not differ from those observed in healthy subjects.     

Absorption of different oral dosage forms of oxycodone in the elderly: a cross-over clinical trial in patients undergoing cystoscopy

Purpose

To characterize the pharmacokinetics (PK) of oxycodone following intravenous injection and administration of three oral dosage forms (solution, capsule, and controlled-release tablet) in elderly patients (age 76–89?years) undergoing cystoscopy.

Methods

This was an open, randomized study with two sequences and two visits in 15 elderly patients. The patients were given intravenous injection (over 10?min) of 5?mg of oxycodone hydrochloride trihydrate. Oxycodone hydrochloride (5?mg in all forms) was orally administered as a solution, a capsule, and a controlled-release tablet. Venous blood samples were collected up to 17?h after oxycodone administration. Population PK parameters were calculated with NONMEM VI 2.0. For intravenous injection we calculated clearance, volume of distribution at steady state, and the half-life of elimination, and for oral dosage forms also the absolute bioavailability.

Results

Clearance of the intravenous injections was 28.9?L/h; the volume of distribution at steady state and the half-life of elimination were 186?L and 5.2?h, respectively. The absolute bioavailability of oxycodone was 59?% from oral solutions, 64?% from capsules, and 55?% from controlled-release tablets.

Conclusions

Our results indicate that, in the elderly, the bioavailability of the three different oral dosage forms of oxycodone is fairly similar.     

In vivo evaluation of hydrochlorothiazide liquisolid tablets in beagle dogs

This study was carried out to evaluate the absorption characteristics of experimentally developed hydrochlorothiazide liquisolid tablets using six male beagle dogs. Comparison with reference commercial tablets was made. As no bibliographic data were found for the pharmacokinetic parameters of the drug in dogs, an intravenous drug administration was included in the study. The drug was administered orally as a single 25 mg dose of commercial and liquisolid tablets on two occasions in a randomized two-way crossover design. The pharmacokinetic parameters of the drug post intravenous dosing were reported for the first time. The results of the oral administration revealed statistically significant differences between the liquisolid and the commercial tablets in the area under the plasma concentration-time curve, the peak plasma concentration, and the absolute bioavailability. On the other hand, no significant differences were observed between the two formulations with regard to the mean residence time, the mean absorption time, and the rate of absorption. The absolute bioavailability of the drug from the liquisolid tablets was 15% higher than that from the commercial one. The parametric 90% confidence intervals for the different parameters were higher than the commonly expected intervals for bioequivalency, indicating greater bioavailability of the liquisolid tablets.     

Pharmacoscintigraphic assessment of the regional drug absorption of the dual angiotensin-converting enzyme/neutral endopeptidase inhibitor,M100240, in healthy volunteers

M100240 is the thioester of MDL 100,173, a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor currently in phase II development. The purpose of this study was to evaluate the relative bioavaibility of M100240 in various regions of the gastrointestinal tract using the Enterion capsule, a noninvasive radiocontrolled device providing targeted drug delivery, to explore the absorption characteristics of M100240 in healthy volunteers. In addition, the absolute bioavailability of an immediate-release formulation of M100240 was assessed. Pharmacokinetic data were obtained from 13 healthy subjects in an open-label, single-dose, randomized, five-period crossover study. Treatments included 25 mg M100240 administered via short intravenous infusion, oral immediate-release tablet administration, and oral Enterion capsule delivery of drug substance to the proximal small bowel, distal small bowel, and ascending colon. Each treatment was separated by a 14-day drug-free washout period. The localization of the Enterion capsule in the gastrointestinal tract was monitored using scintigraphic imaging. M100240 and MDL 100,173 plasma concentrations were quantified using a validated LC/MS/MS method, and pharmacokinetic parameters were calculated using noncompartmental methods. The estimates of relative bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the oral immediate-release tablet are approximately 94%, 97%, and 41%, respectively. M100240 is primarily absorbed throughout the proximal and distal small bowel with modest absorption in the ascending colon. The absolute bioavailability estimate of the M100240 immediate-release formulation is 49%. These data characterize the fundamental in vivo performance attributes of M100240, thereby providing an approach for optimizing prototype modified-release formulations for this compound.     

Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion

The purpose of this study was to investigate the absolute bioavailability of a single oral dose of imatinib (Glivec), 400 mg (capsules vs. oral solution), compared with imatinib, 100 mg (intravenous [i.v.] infusion), in healthy subjects. Twelve subjects received a single treatment in each treatment period: a 400-mg oral dose of imatinib in capsule form or as a solution or a 100-mg i.v. infusion of imatinib. Plasma imatinib concentrations were measured following each treatment; pharmacokinetic parameters and absolute bioavailability were determined. Absolute bioavailability values (compared with i.v. infusion) for the imatinib capsule and oral solution were 98.3% and 97.2%, respectively. Both the rate and extent of imatinib absorption, as measured by C(max), partial AUC, and total AUC, were similar for the oral solution and the imatinib capsule intended for the market. The 400-mg oral dose of imatinib, as a capsule or a solution, was completely absorbed and was almost completely bioavailable (> 97%).     

Pharmacokinetics of three formulations of ondansetron hydrochloride in healthy volunteers: 24-mg oral tablet, rectal suppository, and i.v. infusion.

The absolute bioavailability and pharmacokinetics of three formulations of ondansetron hydrochloride 24 mg--an oral tablet, an intravenous solution, and an extemporaneous rectal suppository--were studied. Twelve healthy, nonsmoking volunteers (six men and six women) were given ondansetron in a study with a three-way cross-over design. All subjects received each dosage form on the same day in the following order: oral tablet, rectal suppository, and intravenous infusion. Administrations were separated by one week. Blood sampling times varied, depending on the administration route. Mean absolute bioavailability for the oral tablet and the rectal suppository differed significantly. Absorption of ondansetron was prolonged when it was administered as the rectal suppository. Absolute bioavailability for the 24-mg tablet was similar to that for other tablet strengths in previous studies. All subjects completed the study without significant adverse effects. Absorption of ondansetron from the rectal suppository was prolonged compared with the oral tablet and the i.v. infusion. Bioavailability for the 24-mg suppository formulation was considerably lower than for the 24-mg tablet.     

Comparison of inter- and intra-subject variation in oral absorption of theophylline from sustained-release products

A comparative study of inter- and intra-subject variation in the bioavailability of theophylline from two commercial sustained-release dosage forms (a beaded capsule and a tablet formulation) was performed in 12 healthy adult volunteers. The disposition kinetics of theophylline was characterized in each subject following a single 250 mg oral dose of a fully bioavailable liquid formulation. Duplicate single dose studies of each of the two sustained-release products were then performed on 4 separate occasions in a randomized crossover fashion. On the average, the extent of theophylline bioavailability from the two sustained-release dosage forms was equivalent and essentially complete as compared to that from the liquid formulation. Both sustained-release formulations exhibited reasonable consistency in the extent of bioavailability when tested on two different trial days in a given subject (the mean percentage difference in extent of absorption was 11.5 ± 8.3% for the beaded capsule and 11.8 ± 12.3% for the tablet). The rate of theophylline absorption from the beaded capsule formulation was more rapid than from the tablet formulation as indicated by an earlier time to reach peak serum concentration (6.0 ± 1.9 vs 8.9 ± 2.5 h). Individual time course of cumulative absorption from the sustained-release formulations was determined using the Wagner-Nelson procedure. The overall variability in the cumulative absorption profile was greater for the tablet as compared to the capsule formulation. More significant was the fact that within each subject the absorption profiles were less reproducible between trials with the tablet as compared to the capsule. Dose-to-dose variation in the release/absorption kinetics of theophylline from these sustained-release products may lead to unpredictable fluctuations in steady-state serum theophylline concentration-time profiles during chronic drug administration.     

Comparative bioavailability of silibinin in healthy male volunteers

AIM: To study a comparative bioavailability of Liverman capsule to Legaion capsule and Silymarin tablet (which contain silibinin) in 24 healthy volunteers. VOLUNTEERS AND METHODS: Twenty-four healthy male Korean volunteers received each medicine at the silibinin dose of 120 mg in a 3 x 3 crossover study. There was a 1-week washout period among the doses. Plasma concentrations of silibinin were monitored by a high-performance liquid chromatography for over a period of 12 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the trapezoidal rule extrapolation method. Cmax (maximum plasma drug concentration) and tmax (time to reach a Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf, AUC(0-12h), and Cmax and untransformed tmax. RESULTS: After an oral administration of Liverman capsule, the pharmacokinetic parameters of silibinin, such as AUC(0-12h) (5.59, 4.24 and 13.9 microg/ml x h for Legalon capsule, Silymarin tablet and Liverman capsule, respectively) and AUCinf (6.00, 4.63 and 15.1 microg/ml x h) were significantly greater, Cmax (1.33, 1.13 and 6.04 microg/ml) was significantly higher and tmax (1.83, 2.10 and 0.875 h) was significantly faster than those after Legalon capsule and Silymarin tablet. CONCLUSION: These results indicate that the absorption and the extent of relative oral bioavailability of silibinin after Liverman capsule were significantly faster and greater, respectively, than those after Legalon capsule and Silymarin tablet.     

Bioavailability and kinetics of cibenzoline in patients with normal and impaired renal function

To test the hypothesis that renal failure alters the disposition of cibenzoline in humans, an absolute bioavailability and elimination kinetic study was performed. We used the simultaneous administration of a stable isotope variant (SASIV). Eight healthy volunteers and eight matched hemodialysis patients each received simultaneously an 80-mg intravenous infusion of 15N-2-cibenzoline and a single 80-mg cibenzoline capsule. Cibenzoline plasma concentrations were assayed by a gas chromatographic-mass spectrometric assay. A compartment-independent kinetic analysis showed a plasma clearance of 707 mL/min and an elimination half-life of 7.3 hours after the intravenous dose in healthy volunteers. In renal-failure patients, cibenzoline clearance decreased to 224 mL/min and half-life increased to 22.4 hours. Decreased plasma clearance was due to decreases in both renal and nonrenal clearance. Absolute bioavailability was 83% and 90% in healthy volunteers and renal-failure patients, respectively. Hemodialysis accounted for only 13% of drug clearance.     

Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate

In vivo study was performed to determine the tolerability and pharmacokinetics of ISIS 104838, a phosphorothioate antisense oligonucleotide targetting human tumour necrosis factor alpha (TNF-alpha) mRNA, following multi-dose administration via intravenous and oral routes. Oral tablet formulations of ISIS 104838 were pre-formulated with the permeation enhancer, sodium caprate, in an enteric-coated solid dosage form. The average plasma bioavailability of ISIS 104838 was 1.4% relative to IV. The tissue distribution profile was similar following both routes of administration, with highest concentrations observed in the kidney followed by the liver, lymph nodes and spleen. Plasma bioavailability underestimated the tissue accumulation of ISIS 104838 observed 1 day after the last dose. Mean systemic tissue bioavailability ranged from 2.0 to 4.3%, relative to IV tissues, and was dependent on tissue type. No marked differences were noted in the pharmacokinetic parameters following multi-dosing either via intravenous or oral routes. All formulations administered were well tolerated. This paper reports the first evaluation of solid oral dosage forms comprising sodium caprate and an antisense oligonucleotide. Furthermore, this study demonstrates the oral delivery of ISIS 104838 from solid oral dose formulations, with the achievement of comparable tissue concentrations of the oligonucleotide to that of the intravenous treatment.     

Bioavailability of pseudoephedrine from controlled release formulations in the presence of guaifenesin in human volunteers

A multiple-dose bioequivalence study with six healthy human volunteers was conducted. The bioavailability of an experimental controlled release tablet containg pseudoephedrine was compared with a marketed controlled release pseudoephedrine capsule in a three-way crossover study. Plasma samples, collected serially after oral drug administrtion, were analyzed for pseudoephedrine content using a specific HPLC method with UV detection. The bioavailability parameters, area under the concentration-time curve (AUC), maximum plasma concentraton C_max, and time to peak (T_max) were obtained from the plasma concentraton—time data. Additionally, model independent pharmacokinetic parameters were estimated. Analysis of variance of the data revealed no statistically significant differences between the test and the reference formulation. The presence of guaifenesin in the sustained release tablet did not influence pseudoephedrine bioavailability. The relative bioavailability of the tablet dosage form with respect to the capsule was found to be 100.8%. Classical and Westlake 95% confidence limits as well as the two one-sided t test, proposed by Schuirmann, and the Anderson—Hauck power analysis supported the inference that the two formulations demonstrated comparable bioavailability, even in the presence of guaifenesin. Using a non-linear regression program, it was found that the parmacokinetics of pseudoephedrine followed a simple one-compartment disposition model with no lag time. Additionally, an in vitro—in vivo correlation, based on the estimation of cumulative relative fraction absorbed, was developed between the absorption of pseudoephedrine in humans and the in vitro dissolution time.     

2种佐米曲普坦制剂人体生物等效性研究

目的:比较国产佐米曲普坦胶囊与进口佐米曲普坦片剂的人体生物等效性。方法:18名志愿者随机交叉单次口服佐米曲普坦胶囊或片剂10mg后,采用高效液相色谱法测定血药浓度,用3p97软件包计算二者的药动学参数和生物等效性。结果:胶囊与片剂的药-时曲线均为口服吸收一室摸型。t1/2ke分别为(3.72±1.77)、(3.81±1.44)h,tmax分别为(1.42±0.35)、(1.33±0.51)h,Cmax分别为(21.68±8.67)、(21.86±10.38)μg/L,AUC(0～T)分别为(75.94±31.34)、(78.40±28.21)(μg.h)/L。佐米曲普坦胶囊的相对生物利用度为(96.86±13.36)%,经方差分析、双单侧t检验及(1～2α)置信区间法统计分析,2种制剂药动学参数无显著性差异(P>0.05)。结论:佐米曲普坦胶囊与片剂具有生物等效性。     

依非韦伦两种剂型在健康人体的药动学和相对生物利用度

目的:研究依非韦伦片剂和胶囊剂的健康人体药动学和相对生物利用度。方法:采用高效液相色谱法测定20名健康志愿者单剂量、自身交叉口服依非韦伦胶囊剂和片剂各600 mg后血浆中依非韦伦浓度。用DAS药动学软件进行药动学参数计算及生物等效性评价。结果:胶囊剂和片剂依非韦伦主要药动学参数如下:Cmax分别为(2.5±0.3)mg.L-1和(2.6±0.5)mg.L-1;tmax分别为(3.05±0.08)h和(3.0±0.7)h;T1/2分别为(38.5±3.3)h和(39.8±6.5)h;AUC0-t分别为(163.3±21.1)mg.h.L-1和(157.6±24.2)mg.h.L-1;AUC0-∞分别为(165.5±23.9)mg.h.L-1和(162.6±23.4)mg.h.L-1。与胶囊剂相比,片剂的相对生物利用度F0-t为(95.3±10.9)%,F0-∞为(96.3±11.3)%。经方差分析和双向单侧t检验,两剂型间的主要药动学参数无明显差异(P>0.05)。结论:建立的方法适用于依非韦伦药动学研究,依非韦伦两种剂型具有生物等效性。     

Absolute intramuscular, oral, and rectal bioavailability of alizapride

A study was designed to estimate the absolute bioavailability of alizapride after intramuscular injection, oral administration as a solution or a tablet, and rectal administration as a suppository compared with that after intravenous injection. A balanced incomplete block-design trial was adopted. The intramuscular injection and the tablet administration showed identical results with those of the intravenous injection. On the contrary, the oral solution and the rectal suppository dosage forms gave lower absorption values, i.e., 75 and 61% of the dose administered was absorbed, respectively.     

乳酸司氟沙星片人体生物等效性研究

目的 :研究乳酸司氟沙星片在健康人体内的药代动力学与相对生物利用度 ,以评价其生物等效性。方法 :采用高效液相色谱法测定10名健康志愿者随机交叉口服单剂量 (400mg)乳酸司氟沙星片与参比制剂 (司帕沙星片 )后血浆中司帕沙星的药 -时数据 ,经3p97药代动力学程序拟合 ,计算其药代动力学参数并评价其生物等效性。结果 :乳酸司氟沙星片与司帕沙星片的主要药代动力学参数分别为 :T1/2β= (22 05±1 70)h、(22 23±1 77)h ;Cmax = (1 80±0 16) μg/ml、(1 74±0 16) μg/ml ;Tmax = (4 11±0 68)h、(3 96±0 80)h ;AUC0～t= (49 12±4 53)h/ (μg·ml)、(45 82±5 32)h/ (μg/ml)。乳酸司氟沙星片的相对生物利用度为(107 57±8 47) %。结论 :乳酸司氟沙星片与参比制剂司帕沙星片为生物等效制剂     

Bioavailability of silicon and aluminum from Zeolite A in dogs

A study in beagle dogs was carried out to estimate the bioavailability of silicon and aluminum from Zeolite A administered as a capsule, oral suspension, and oral solution relative to an intravenous bolus infusion (i.v.) administered over a 1-1.5 min interval. Twelve dogs received single doses of Zeolite A after a 1 week control period in a randomized five-way crossover design. Plasma samples were drawn at time 0 and for 36 h after dosing. The concentrations of silicon and aluminum were determined by graphite furnace atomic absorption at the University of North Carolina School of Medicine (Bioanalytical Laboratory, UNC). The plasma silicon and aluminum data from i.v. infusion were best described by two-compartment and three-compartment open models, respectively. The mean elimination half-life and clearance of silicon from the i.v. dose were 17.5 h and 0.221 ± 0.0192 ml/min per kg. The mean extent of absorption of silicon from the oral capsule, oral solution and oral suspension was 2.33%, 3.44% and 2.73%, respectively, relative to the intravenous bolus. The mean elimination half-life and clearance of aluminum were 91.2 h and 0.0497 ± 0.0082 ml/min per kg. The extent of absorption of aluminum from the oral dosage forms was less than 0.1%, relative to the intravenous infusion. The plasma aluminum AUC values from the oral capsule and suspension showed no statistical difference from those during the control period, but the aluminum AUC of the oral solution was statistically greater than the AUC of the corresponding control period.     

国产罗红霉素胶囊和片剂的药物动力学和生物利用度比较

目的：比较罗红霉素胶囊和片剂的生物利用度和药物动力学。方法：８ 名健康志愿者单剂量口服３００ｍ ｇ 罗红霉素胶囊和片剂,微生物法测定血药浓度。结果：罗红霉素胶囊和片剂的血药浓度－ 时间曲线符合二室模型,Ｃｍ ａｘ 分别为（１０－１４ ±１－６６） 和（１０－０２ ±１－８４）μｇ／ ｍｌ ;Ｔｍ ａｘ 分别为（１－４４ ±０－３２） 和（１－３１ ±０－２６）ｈ ;ＡＵＣ 分别为（７９－８７ ±１６－２２） 和（７３－８６ ±１３－４６）ｈ／（μｇ ·ｍｌ） 。结论：两种制剂药物动力学参数无显著性差异,罗红霉素胶囊和片剂具有生物等效性,胶囊相对于片剂的生物利用度为（１０９ ±１５） ％ 。     

Pharmacokinetics of bumetanide following intravenous, intramuscular, and oral administrations to normal subjects

The pharmacokinetics of bumetanide was studied in 12 normal subjects after 1-mg intravenous, intramuscular, oral solution, and tablet administrations in a random four-treatment crossover design. Plasma and urine concentrations of intact bumetanide were analyzed by a sensitive and specific RIA. The pharmacokinetics of bumetanide after intravenous administration was characterized by a biexponential equation, including an initial disposition phase (t 1/2, alpha = 5.1 min), followed by a slower elimination phase (t 1/2, beta = 44 min). Bumetanide pharmacokinetics after intramuscular and oral administration could be described by a biexponential equation with first-order absorption and elimination. Bumetanide is rapidly absorbed via the intramuscular and oral routes, with mean +/- SD maximum plasma concentrations of 38.2 +/- 9.8 (intramuscular), 34.0 +/- 10.6 (oral solution), and 30.9 +/- 14.6 ng/mL (tablet) achieved within 0.34 +/- 0.23, 0.76 +/- 0.27, and 1.8 +/- 1.2 h after dosing, respectively. The drug is rapidly eliminated from the body after intravenous, intramuscular, oral solution, and oral tablet administrations, with half-lives ranging from 24-86, 47-139, 27-71, and 26-99 min, respectively. Approximately 70% of a parenteral dose and 60% of an oral dose are excreted as intact drug in urine taken 0-24 h after administration. The extent of bioavailability of bumetanide from the tablet and oral solution dosage forms are equivalent, and the absolute bioavailability of the intramuscular and oral preparations are approximately 100 and 80%, respectively. This is consistent with the predicted limited extent of first-pass metabolism after complete absorption of an oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and clinical pharmacokinetics of microcrystalline theophylline

Summary Variation in the systemic disposition of theophylline after ingestion of a new microcrystalline product (Theolair®) has been investigated in 7 hospitalized patients with generalized obstructive lung disease. Disposition (absolute bioavailability) was determined by comparing in the same patients the areas under the serum concentration-time curves after a single oral dose of microcrystalline theophylline and after an intravenous infusion of aminophylline. Oral absorption appeared to be fast. The half-life of absorption was 19±9 min (mean±SD). Maximal serum concentrations reached after 100±30 min were found to be in a rather narrow range: 9.8±2.5 mg · 1^–1. The absolute bioavailability of the microcrystalline preparation was high and it showed only small variation: 102.7±10.2% of the dose. Relevant pharmacokinetic parameters (half-life of elimination, volume of distribution and total body clearance) were determined after both routes of administration. Individual dosage regimens required to obtain a therapeutic serum concentration were calculated for each individual patient on the basis of the observed pharmacokinetic parameters.     

Pharmacokinetics of raclopride formulations. Influence of prolactin and tolerability in healthy male volunteers.

The pharmacokinetic and pharmacodynamic properties of raclopride, a new antipsychotic, were investigated in 16 healthy men. Single 4 mg doses were administered as intravenous infusion, oral solution and 2 extended release (ER) formulations. Total plasma clearance was about 100 ml/min (6.0 L/h), of which renal clearance accounted for 0.2 ml/min, indicating extensive metabolism. The volume of distribution was 1.5 L/kg; mean absolute bioavailability was 65 to 67% following the oral solution and the ER formulations. A transient increase in plasma prolactin levels followed both the intravenous infusion and the oral solution. The ER formulations resulted in a lower increase, which appeared later. However, the area under the prolactin level curve was similar after administration of all dosage forms. The frequency and severity of the most commonly reported side effects (tiredness and restlessness) were higher after the intravenous infusion than after the ER capsules. These findings indicate that such capsules may be advantageous for clinical antipsychotic treatment with raclopride.