Bioavailability and pharmacokinetics of a praziquantel bolus in kingfish Seriola lalandi

Oral praziquantel (PZQ) preparations have recently been investigated for the treatment of monogeneans that infect the skin and gills of kingfish Seriola lalandi cultured in sea-cages. To evaluate an oral PZQ dosing strategy, the pharmacokinetics of a dissolved and in feed oral PZQ preparation (40 mg kg(-1) body weight) were compared with an intravenous bolus in kingfish plasma and skin using HPLC. Compared with intravenous administration, PZQ bioavailability (area under curve, AUC0-24h) was slightly improved when the drug was administered with food in both kingfish plasma (56.8% in feed vs. 50.8% in solution) and skin (55.5% in feed vs. 50.3% in solution). After oral dosing, maximum drug concentrations in skin were approximately one-third of those achieved in plasma and higher when the drug was administered in solution (5.26 microg ml(-1)) than in feed (3.96 microg ml(-1)); additionally, the time to achieve maximum PZQ concentration was similar in plasma and skin, although markedly reduced when the drug was administered in solution (1 h) than in feed (6 h). However, clearance of the drug was delayed in skin; administered as an oral formulation, PZQ concentrations in the systemic circulation fell below the limit of quantification after 24 h, but remained quantifiable (0.3 microg g(-1)) in skin at this time. These initial studies indicate that a daily treatment interval will lead to the exposure of parasites to highly variable anthelmintic concentrations, which may be sub-optimal for the treatment of monogeneans in this finfish species.     

Comparative bioavailability of three brands of ampicillin

The relative biological availability (bioavailability) of three brands of ampicillin trihydrate capsules marketed in Canada was studied by means of a crossover experimental design and was evaluated by analysis of variance. After administration of a single oral dose (500 mg.) to volunteer subjects, the mean peak ampicillin serum concentration and the area under the time ampicillin serum concentration curve (AUC) were higher for one of the products than for the other two. A second study utilizing the same experimental design revealed no differences in these parameters when different production lots of the more available product were compared. Product bioavailability was not related to the in vitro dissolution time of the capsules. The experimental design and methods of statistical analysis are discussed.     

孟鲁斯特钠咀嚼片在健康人体内药动学和生物等效性

目的:研究两种(仿制新药与市售)孟鲁司特钠咀嚼片在人体内生物等效性。方法:采用单中心、随机、开放、双周期自身交叉试验设计,20名健康男性志愿者分2周期分别口服受试制剂和参比制剂各10 mg,HPLC法测定血浆中孟鲁司特钠咀嚼片的浓度,用DAS2.1.1软件计算人体药动学参数并进行生物等效性评价。结果:受试制剂和参比制剂两药的主要药代动力学参数AUC0-t分别为(17.94±6.19)μg h/ml和(17.37±4.73)μg h/ml,AUC0-∞分别为(18.26±6.16)μg h/ml和(17.64±4.66)μg h/ml,Cmax分别为(5.58±1.95)μg/ml和(5.54±1.65)μg/ml,Tmax分别为(2.03±0.97)h和(1.93±0.69)h,t1/2分别为(1.20±0.17)h和(1.19±0.13)h。受试制剂的平均相对生物利用度为(101.5±6.56)%。结论:受试制剂和参比制剂具有生物等效性。     

Differential stereoselective pharmacokinetics of pantoprazole,a proton pump inhibitor in extensive and poor metabolizers of pantoprazole—a preliminary study

Pantoprazole (PAN) is a proton pump inhibitor that is administered as a racemic mixture. The pharmacokinetics of PAN enantiomers were investigated in extensive metabolizers (EMs) and apparent poor metabolizers (PMs) of PAN who received a single 40, 60, or 80 mg oral dose of racemic PAN as enteric-coated formulation. In the EMs, the serum concentrations of (−)-PAN were slightly higher than those of (+)-PAN at each dose level. The (+)/(−) ratios for the area under the concentration-time curve (AUC) and the half-life were 0.58–0.89 and 0.62–0.88, respectively. In the PMs, the serum concentrations of both enantiomers were much higher than those in the EMs at each dose level and significant differences in pharmacokinetics of (+)- and (−)-PAN were observed. The half-lives for (+)-PAN were 2.67–3.77 times longer than those for (−)-PAN. The AUCs for (+)-PAN were 2.65–3.45 times greater than those for (−)-PAN. Therefore, the metabolism of (+)-PAN is impaired to a greater extent than (−)-PAN in the PMs, which resulted in the stereoselective disposition of PAN in the PMs. It has been suggested that the EMs and the PMs of PAN could be differentiated by determining the (+)/(−) enantiomer ratio in serum at one time point, possibly 2–6 h after oral dosing, because the (+)/(−) enantiomer ratios in the PMs were opposite those in the EM subjects. Chirality 9:17–21, 1997 © 1997 Wiley-Liss, Inc.     

Pharmacokinetic data of propranolol enantiomers in a comparative human study with (S)- and (R,S)-propranolol

The pharmacokinetics of (S)-propranolol were compared after the oral administration of a 40 mg dose of the pure enantiomer and an 80 mg dose of a racemic mixture of (R,S)-propranolol. The results of this study indicate that the bioavailability of (S)-propranolol, as expressed by the mean area under the concentration-time curve (AUC) and maximum serum concentration, is lower after 40 mg of the optically pure drug than after the racemic drug.     

Pharmacokinetics of an injectable long-acting formulation of doxycycline hyclate in dogs

ABSTRACT: Based on its PK/PD ratios, doxycycline hyclate (DOX-h), a time-dependant antibacterial, is ideally expected to achieve both sustained plasma drug concentrations at or slightly above the MIC level for as long as possible between dosing intervals. Pursuing this end, a poloxamerbased matrix was used to produce a long-acting injectable preparation (DOX-h-LA) and its serum concentrations vs. time profile investigated after its SC injection to dogs ([less than or equal to] 0.3 mL per injection site), and results compared with the oral (PO) and IV pharmacokinetics of DOX-h, prepared as tablet or as freshly made solution. A crossover (4 x 4 x 4) study design was employed with 12 Mongrel dogs, with washout periods of 21 days, and at dose of 10 mg/kg in all cases. DOX-h-LA showed the greatest values for bioavailability (199.48%); maximum serum concentration (Cmax) value was 2.8 +/- 0.3 with a time to reach Cmax (Tmax) of 2.11 +/-0.12 h and an elimination half-life of 133.61 +/- 6.32 h. Considering minimum effective serum concentration of 0.5 mug/mL, a dose-interval of at least 1 week h can be achieved for DOX-hLA, and only 48 h and 24 h after the IV or PO administration of DOX-h as a solution or as tablets, respectively. A non-painful small bulge, apparently non-inflammatory could be distinguished at injection sites. These lumps dissipated completely in 30 days in all cases.     

Novel insulin thiomer nanoparticles: in vivo evaluation of an oral drug delivery system

It was aim of the study to investigate the in vivo potential of a novel insulin-thiomer complex nanoparticulate delivery system. Insulin loaded nanoparticles were obtained by the formation of hydrogen bonds between poly(vinyl pyrrolidone) (PVP) and poly(acrylic acid)-cysteine (PAA-Cys) or poly(acrylic acid) (PAA), respectively, in the presence of insulin. Dissolution behavior of insulin from tablets as well as nanoparticulate suspensions was evaluated in vitro. Serum insulin concentrations and reduction of blood sugar values were determined after oral administration of nanoparticles formulated as enteric coated tablets and suspensions. Results displayed a low serum insulin concentration and pharmacological efficacy in terms of blood sugar reduction after oral administration of enteric coated tablets. On the contrary, nanoparticulate suspensions led to significant serum insulin concentrations. Furthermore a 2.3-fold improvement of the AUC of insulin could be achieved due to the use of thiolated PAA instead of unmodified PAA. In addition, a blood sugar reduction of 22% was observed. Results demonstrate that this novel complex nanoparticulate formulation is an encouraging new attempt toward the noninvasive delivery of peptide drugs.     

Day-Night Differences in Steady-State Theophylline Pharmacokinetics in Asthmatic Children

Potential day-night differences of theophylline absorption and disposition were examined in day-active asthmatic children. Theophylline was given orally as TheoDur tablets and Somophyllin-CRT capsules (random crossover) every 12 hr (0700 and 1900), and patients were studied during two consecutive dosing intervals. In addition, patients were studied during the last 24 hr of a 48-hr continuous, intravenous aminophylline infusion. Serum theophylline concentrations were essentially constant during the intravenous infusion for the day and night periods. Thus, day and night clearances were nearly identical. Following oral administration of Somophyllin-CRT or TheoDur, areas under the serum concentration-time curves were greater during the day than the night, with Somophyllin-CRT yielding greater areas than TheoDur for both dosing intervals. Theophylline was absorbed more rapidly during the day than the night, as evidenced by a time to maximum concentration that occurred earlier in the daytime dosing interval. We conclude that theophylline clearance is not characterized by a circadian rhythm and that absorption of theophylline from Somophyllin-CRT and TheoDur is more rapid and complete during the day than the night.     

Concentration of ethinyl estradiol in the serum of 31 young women following a treatment period of 3 months with two low-dose oral contraceptives in an intraindividual cross-over design.

Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE2) but different progestins (gestodene and desogestrel, respectively), were compared with respect to the relative bioavailability of EE2. The study was conducted with 31 women as an open intraindividual comparison with the ingestion of both preparations for 3 months, respectively. On days 1, 10 and 21 of the 1st, 3rd and 6th cycle, blood was sampled at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h following administration. The concentrations of EE2 were determined in the serum samples of each individual and the area under the serum concentration versus time curves, AUC (0-4 h) and AUC (0-24 h), were calculated. Corresponding parameters obtained on days 1, 10 and 21 of the 3rd and 6th month of treatment were compared on a statistical basis, and no differences were found. This result was in concordance with a previously performed study, where both formulations were administered to 18 women in a single-dose cross-over design. However, the results of the previous and the present study are at variance with the result of one other study, reporting higher EE2 levels in the serum of women taking the gestodene-containing formulation as compared to those taking the desogestrel-containing formulation.     

Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension

Pharmacokinetic and pharmacodynamic interactions between simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and diltiazem, a calcium antagonist, were investigated in 7 male and 4 female patients with hypercholesterolemia and hypertension. The patients were given, for one in a three consecutive 4-week periods, oral simvastatin (5 mg/day), oral simvastatin (5 mg/day) combined with diltiazem (90 mg/day), and then oral diltiazem (90 mg/day), respectively. The area under the plasma concentration versus time curve up to 6 hours post-dose (AUC0-6h) and maximum plasma concentrations (Cmax) of the drugs, serum lipid profiles, blood pressures and liver functions were assessed on the last day of each of the three 4-week periods. After the combined treatment period, Cmax of HMG-CoA reductase inhibitor was elevated from 7.8 +/- 2.6 ng/ml to 15.4 +/- 7.9 ng/ml (P < 0.01) and AUC0-6h from 21.7 +/- 4.9 ng x hr/ml to 43.3 +/- 23.4 ng x hr/ml (P < 0.01), while Cmax of diltiazem was decreased from 74.2 +/- 36.4 ng/ml to 58.6 +/- 18.9 ng/ml (P < 0.05) and its AUC0-6h from 365 +/- 153 ng x hr/ml to 287 +/- 113 ng x hr/ml (P < 0.01). Compared to simvastatin monotherapy, combined treatment further reduced LDL-cholesterol levels by 9%, from 129 +/- 16 mg/dl to 119 +/- 17 mg/dl (P < 0.05). No adverse events were observed throughout the study. These apparent pharmacokinetic interactions, namely the increase of HMG-CoA reductase inhibitor concentration by diltiazem and the decrease of diltiazem concentration by simvastatin, enhance the cholesterol-lowering effects of simvastatin during combined treatment.     

Bioavailability study of dried microencapsulated ferrous sulfate — SFE 171 — by means of the prophylactic-preventive method

Microencapsulated ferrous sulfate with soy lecithin (SFE-171) has been used as an iron source for the fortification of milk and dairy products. With the purpose to extend the use of this agent to other kind of foods or even to pharmaceutical preparations for oral administration, the SFE-171 was turned into a fluid powder (SFE-171-P) by means of vacuum drying. The iron bioavailability (BioFe) of SFE-171-P was evaluated in this work by means of the prophylactic-preventive method in rats, using ferrous sulfate as reference standard. Both iron sources were separately added to a basal diet of low iron content in a concentration of 10 mg iron/kg diet. Two groups of 10 weaned rats 25 days old received the fortified diets during 28 days, while a third group of the same size received the basal diet without iron additions. The weights and haemoglobin concentrations (HbC) of every animal were determined before and after the treatment, thus allowing the calculation of the mass of iron incorporated into haemoglobin (HbFe) during this period. The BioFe of the iron sources were obtained as the percentage ratio between the HbFe and the mass of iron consumed by each animal. The results were also given as Relative Biological Value (RBV), which relates the BioFe of the studied source with that of the reference standard. The liver iron concentration (LIC) of each animal was determined at the end of the experiment in order to evaluate the influence of the studied iron sources on the liver iron stores. SFE-171-P presented BioFe, RBV and LIC values of (47 ± 7) %, 109% and (46.6 ± 3.4) mg/kg respectively, while the corresponding values for the reference standard were of (43 ± 7)%, 100% and (45.0 ± 4.7) mg/kg. These results show that the drying process used to produce the SFE-171-P does not affect its bioavailability, which is also adequate for the potential use of this product in food fortification or with pharmaceutical purposes.     

不同剂量阿伐他汀联合阿司匹林治疗原发性高血压并动脉粥样硬化的临床研究

目的:探讨不同剂量阿托伐他汀联合阿司匹林治疗原发性高血压并动脉粥样硬化的临床疗效。方法:选取2015年1月-2016年12月在我院治疗的原发性高血压并动脉粥样硬化患者80例,随机分为对照组和实验组,每组40例。实验组给予口服高剂量阿托伐他汀(40 mg/d)联合阿司匹林肠溶片(100 mg/d)治疗,对照组给予口服高剂量阿托伐他汀(20 mg/d)联合阿司匹林肠溶片(100 mg/d)治疗,疗程均为3个月。观察和比较两组患者治疗前后的总胆固醇(total cholesterol,TC)、高密度脂蛋白胆固醇(high-density lipoproteincholesterol,HDL-C)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)、收缩压(systolic blood pressure,SBP)、舒张血压(diastolic blood pressure,DBP)以及颈动脉斑块分级。结果:两组治疗后的SBP、DBP、血清TC、TG和LDL-C水平均较治疗前显著降低,血清HDL-C水平较治疗前明显升高,且实验组SBP、DBP、血清TC、TG和LDL-C水平均显著低于对照组(P0.05),血清HDL-C水平明显高于对照组(P0.05)。实验组颈动脉斑块0-Ⅰ级的比例显著高于对照组(P0.05)。结论:口服高剂量阿托伐他汀(40 mg/d)联合阿司匹林肠溶片(100 mg/d)治疗原发性高血压并动脉粥样硬化较低剂量阿托伐他汀(20 mg/d)联合阿司匹林肠溶片(100 mg/d)疗效更好,可以有效降低血压,调节血脂并改善患者预后。     

Eudragit L/HPMCAS Blend Enteric-Coated Lansoprazole Pellets: Enhanced Drug Stability and Oral Bioavailability

The objectives of the present work were to use blends of Eudragit L and hydroxypropyl methylcellulose acetate succinate (HPMCAS) as enteric film coatings for lansoprazole (LSP) pellets. The enteric-coated pellets were prepared with a fluid-bed coater. The influence of the blend ratio, type of plasticizer, plasticizer level, coating level, and curing conditions on gastric stability in vitro drug release and drug stability was evaluated. Furthermore, the bioavailability of the blend-coated pellets in beagle dogs was also performed. The blend-coated pellets exhibited significant improvement of gastric stability and drug stability compared to the pure polymer-coated pellets. Moreover, the AUC values of blend-coated pellets were greater than that of the pure polymer-coated pellets. It was concluded that the using blends of Eudragit L and HPMCAS as enteric film coatings for LSP pellets improved the drug stability and oral bioavailability.     

头孢氨苄胶囊制剂人体生物等效性研究

目的:研究新仿制的头孢羟氨苄胶囊制剂与市场在售的同类制剂在健康人体内的生物等效性。方法:采用随机交叉试验设计,20名健康男性志愿者分别口服受试制剂与参比制剂500 mg,HPLC法测定血浆中头孢氨苄的浓度,用DAS 2.0软件计算药动学参数并进行生物等效性评价。结果:受试制剂和参比制剂两药的主要药代动力学参数,Cmax分别为(18.12±3.17)μg/ml和(21.28±3.77)μg/ml,Tmax分别为(1.09±0.37)h和(1.04±0.33)h,t1/2分别为(1.15±0.22)h和(1.14±0.20)h,AUC0-t分别为(35.43±5.39)μg h/ml和(37.27±4.76)μg h/ml,AUC0-∞分别为(36.68±6.06)μg h/ml和(38.62±5.48)μg h/ml,受试制剂的平均相对生物利用度为(96.50±7.2)%。结论:受试制剂和参比制剂具有良好的生物等效性。     

Circadian Rhythm in Serum Iron Levels

This study was aimed at assessing the circadian rhythm of serum iron levels in Chinese healthy subjects. The project was conducted in 19 healthy, Chinese male subjects following a 4-day diet equilibration. Blood samples were collected on day 5 at 0800, 1000, 1200, 1400, 1600, 1800, 2000, and 2400 hours to determine endogenous serum iron concentrations. Iron concentrations were determined using an inductively coupled plasma mass spectrometry. Iron concentration was decreased from morning to afternoon. The minimum value of iron level was 1,987 μg/L at 2000 hours while the maximum was 2,229 μg/L at 1000 hours, and 2,278 μg/L at 1400 hours, respectively, the amplitude was 291 μg/L. This study indicates that when assessing the bioequivalence of iron formulations, baseline levels of iron (obtained before dosing) should not be subtracted simply from the amount obtained on the drug dosing day to yield the net effect of iron formulation administration. More valid methods to optimize the design of such bioequivalence studies should be taken into consideration.     

Serum lipids in 8- to 35-day-old Zucker rats

The serum concentrations of triacylglycerols, cholesterol, and phospholipids were measured in 8- to 35-day-old Zucker rats. The animals were killed at 35 days of age. and their phenotype is determined on the basis of the weight of their inguinal subcutaneous fat pads. The serum lipid concentrations in all the rats increased from the 8th day of life, reaching a maximum at day 17 to 21. Weaning produced a large decrease in the concentrations of all three types of lipids. In the obese rats, the serum concentration of triacylglycerols was significantly raised from day 35 of life, that of cholesterol from day 21, and that of phospholipids from as early as day 8. At this age this latter concentration nevertheless cannot be used as a factor for detecting the obese phenotype.     

Nanomedicines in renal transplant rejection--focus on sirolimus

Nanomedicine, known as the application of nanotechnology in medicine, has been applied to overcome the problems of poor bioavailability, in vitro and in vivo stability, and targeted delivery in the preparation of pharmaceutical products. Sirolimus, a water-insoluble immunosuppressant, has been formulated into an oral solid dosage form by using NanoCrystal technology to increase the water solubility and thereby the bioavailability. The efficacy, safety, and pharmacokinetic properties are not significantly different between liquid and solid formulations except that less fluctuation of sirolimus blood concentration was observed in solid dosage form. The tablet formulation offers the advantages of better palatability and more convenience for long-term use. Sirolimus tablets are not only a successful example of nanomedicine, but also a more cost-effective treatment in renal transplantation than cyclosporine and tacrolimus.     

Development of in vitro pharmacokinetic screens using Caco-2, human hepatocyte, and Caco-2/human hepatocyte hybrid systems for the prediction of oral bioavailability in humans

In this study, in vitro systems were used to build 2 pharmacokinetic models that predict human oral bioavailability: the Caco-2/hepatocyte combination model and the Caco-2/hepatocyte hybrid model. Data obtained in vitro on Caco-2 cell permeability and hepatocyte clearance are routinely used to predict the fraction of absorption after oral administration and the extent of first-pass metabolism, respectively. In the Caco-2/hepatocyte combination model, results from a Caco-2 cell permeability assay and a hepatocyte clearance assay were combined to project oral bioavailability. Comparison of oral bioavailabilities predicted by the combination model and reported oral bioavailabilities in humans for 30 marketed compounds resulted in a modest correlation (r(2) = 0.66). The Caco-2/hepatocyte hybrid model, as previously reported, joins the Caco-2 and hepatocyte clearance systems into 1 assay. Improvements to the previous model were made by incorporating an elimination phase into the Caco-2/hepatocyte hybrid model. In the new hybrid model, the compound was added to a Caco-2-containing donor compartment and allowed to permeate for 2 h to a hepatocyte-containing receiver compartment. Subsequently, to mimic an elimination phase, the donor compartment was removed, and permeated compound was incubated with hepatocytes alone for an additional 3 h. The area under the concentration versus time curve (AUC) was determined for each of the same 30 marketed compounds assessed by the combination model. A linear regression analysis comparing the in vitro AUCs and reported oral bioavailabilities in humans showed a reasonable correlation (r(2) = 0.73). This study demonstrates that the Caco-2/hepatocyte hybrid model is more favorable and further proves the potential and feasibility of using in vitro screenings for the prediction of in vivo pharmacokinetics in humans.     

Oral absorption of phytosterols and emulsified phytosterols by Sprague-Dawley rats

Clinical studies have demonstrated that consumption of phytosterol esters in lipid-based foods decreases serum concentrations of total and LDL cholesterol. These substances represent minimal potential for adverse effects when consumed orally because of their low bioavailability. However, some studies have reported estrogenic and other effects in laboratory animals treated parenterally with phytosterols, demonstrating that these substances may have the potential to cause adverse effects if absorbed. Water-soluble phytosterols have been prepared by formulation with emulsifiers to expand delivery options to include non-lipid-based foods. However, emulsifiers are used as excipients in the formulation of lipophilic pharmaceuticals to increase solubility, thereby increasing their absorption. Therefore, oral consumption of emulsified water-soluble phytosterols could potentially increase their absorption. In the current study, absorption of phytosterols prepared as water-soluble emulsified micelles with two different food-grade emulsifiers was evaluated in Sprague-Dawley rats and compared with absorption of non-micellar free phytosterols and esterified phytosterol mixtures dissolved in a lipophilic vehicle (soybean oil). Rats were dosed via gavage with 42 mg/kg of formulated phytosterol preparations. Blood was collected at 8, 16, 24, and 32 hours, extracted with hexane, derivatized with benzoyl chloride, and analyzed by high-performance liquid chromatography to determine concentrations of beta-sitosterol, and campesterol. Plasma concentrations and AUC(0-32 hours) [microg/mL/h] of beta-sitosterol and campesterol were lower in plasma obtained from rats treated with emulsified phytosterol preparations than in animals treated with free phytosterols dissolved in soybean oil. Because the pharmacokinetic profile of water-soluble phytosterols is similar to that of phytosterols administered in a lipid vehicle, the safety profile is likely to be the same as that of phytosterols and phytosterol esters in currently used applications.     

Effect of ciprofloxacin on steady state pharmacokinetics of phenytoin in rabbits.

Present study was undertaken to determine if an interaction exists during co-administration of ciprofloxacin with phenytoin. Eight healthy male rabbits received oral phenytoin, 40 mg/kg, od, for 7 days. On day 7, phenytoin blood sampling was done at times 0, 0.1, 1, 2, 3, 4, 5, 6, 8 and 24 hr. From day 8 to 14, phenytoin was co-administered with oral ciprofloxacin, 70 mg/kg, od. On day 14, blood samples were collected as previously described. Pharmacokinetic analysis revealed significant decrease in steady state maximum concentration (Cmax), through concentration (Cmin), elimination half life (t 1/2 e) and the area under plasma time concentration curve (AUC0-24) of phenytoin when co-administered with ciprofloxacin. It warrants close monitoring of levels when these two agents are given simultaneously.