Oral bioavailability in pigs of a miconazole/Hydroxypropyl-γ-cyclodextrin/ L-tataric acid inclusion complex produced by supercritical carbon dioxide processing

The objective of this study was to determine the pharmacokinetic parameters of miconazole after oral administration of a miconazole/hydroxypropyl-gamma-cyclodextrin(HPgammaCD)/L-tartaric acid inclusion complex produced by supercritical carbon dioxide processing. The pharmacokinetics of the miconazole ternary complex (CPLX), of the corresponding physical mixture (PHYS), and of miconazole alone (MICO) were compared after oral administration. Six mixed-breed pigs received each formulation as a single dose (10 mg miconazole/kg) in a crossover design. Miconazole plasma concentrations were determined by a high-performance liquid chromatography method. Preliminary in vitro dissolution data showed that CPLX exhibits a faster and higher dissolution rate than either PHYS or MICO. Following CPLX oral administration, mean area under the plasma concentration curve (AUC(0-infinity)) for miconazole was 95.0 +/- 55.8 microg/min/mL, with the peak plasma concentration (C(max) 0.59 +/- 0.39 microg/mL) at 19.30 minutes. The AUC(0-infinity) and C(max) values were significantly higher than those after oral administration of PHYS (AUC(0-infinity) 38.5 +/- 12.7 microg/min/mL and C(max) 0.24 +/- 0.08 microg/mL; P < .1) and of MICO (AUC(0-infinity) 24.1 +/- 14.0 microg/min/mL and C(max) 0.1 +/- 0.05 microg/mL; P < .1). There were also significant differences between PHYS and MICO (P < .1). The results of the study indicate that CPLX shows improved dissolution properties and a higher relative oral bioavailability compared with PHYS and MICO.     

沙丁胺醇气雾剂在健康受试者体内的药物动力学和相对生物利用度

目的:研究沙丁胺醇气雾剂在健康受试者的药物动力学和生物利用度.方法:十名健康男性志愿者单剂量吸入1.2 mg沙丁胺醇气雾剂或口服沙丁胺醇水溶液.用HPLC法测定人血浆中沙丁胺醇浓度.以非房室模型计算药物动力学参数,计算气雾剂相对水溶液的生物利用度.结果:气雾剂和口服溶液的药物动力学参数如下:T_(max)(0.22±0.07)和(1.8±0.6)h,C_(max)(3.4±1.1)和(3.9±1.4)μg·L~(-1),T_(1/2)(4.5±1.5)和(4.6±1.1)h,AUC_(0-20min)(0.9±0.3)和(0.16±0.10)μg·h·L~(-1).两种给药途径的T_(max)和AUC_(0-20 min)之间差异显著(P<0.01).AUC_(0-20min)(nihal)为 AUC_(0-20 min)(po)的 8倍.沙丁胺醇气雾剂相对口服溶液的生物利用度为 57％±24％.结论:沙丁胺醇气雾剂在人体的吸收过程与口服溶液差异有显著性.     

Study on bioavailability difference between clopidogrel bisulfate form I and form II using liquid chromatography/tandem mass spectrometry

The bioavailability of clopidogrel bisulfate (CAS 135046-48-9) form I was compared with that of clopidogrel bisulfate form II in 12 male Sprague-Dawley rats. The rats, randomly divided into two groups, received a single oral dose of 8 mg/kg clopidogrel (CP) bisulfate form I and form II, respectively, under fasting condition. The plasma concentrations of CP and its inactive carboxylic acid metabolite (CAS 144457-28-3, IM) were simultaneously determined by a sensitive, specific LC-MS/MS method. The pharmacokinetic parameters included C(max), T(max), t1/2, AUC(0-t), AUC(0-infinity). The AUC(0-infinity) of CP was 13.78 +/- 0.67 and 11.46 +/- 1.98 ng/ mL x h for CP form I and form II, respectively. The AUC(0-infinity) of IM was 33.08 +/- 5.76 and 21.67 +/- 8.95 microg/mL x h for CP form I and form II, respectively. The maximum plasma concentration (C(max)) of CP was 3.81 +/- 0.54 ng/mL for CP form I and 3.18 +/- 0.31 ng/mL for CP form II, the C(max) of IM was 3.42 +/- 0.41 and 2.08 +/- 0.68 microg/ mL for the CP form I and form II, respectively. There was an obvious difference between form I and form II for C(max) and the area under the plasma concentration time curve for both CP and IM after a t-test. This study shows that CP form I has better bioavailability in rats than CP form II.     

Pharmacokinetics and bioequivalence study of clindamycin hydrochloride formulations after single-dose administration in healthy Chinese male volunteers

The aim of the present study was to compare the bioavailability of clindamycin (CAS 18323-44-9) from three clindamycin hydrochloride (CAS 21 462-39-5) capsules (clindamycin 75 mg capsule as test 1 preparation, 150 mg capsule as test 2 preparation and a commercially available original 150 mg capsule of the drug as reference preparation) in 24 Chinese healthy male volunteers, aged between 22 and 28. The study was conducted according to a randomized, double-blind, 3-period, 3-treatment, 3-sequence, single-dose, crossover design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 14 h post-dose, and clindamycin plasma concentrations were determined with a validated liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Maximum plasma concentrations (C(max)) of 3.06 +/- 1.10 microg/mL (test 1), 3.10 +/- 1.59 microg/mL (test 2) and 3.06 +/- 1.15 microg/mL (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 10.73 +/- 4.29 microg x h/mL (test 1), 10.54 +/- 4.10 microg x h/ mL (test 2) and 11.29 +/- 4.98 microg x h/mL (reference), AUC(0-t) of 10.32 +/- 4.09 microg x h/ mL, 10.26 +/- 3.96 microg x h/mL, 10.94 +/- 4.86 g x h/mL were calculated. The median T(max) was 0.80 +/- 0.52 h, 0.77 +/- 0.37 h, 1.01 +/- 0.6 h for test 1, test 2 and reference formulation, respectively. Plasma elimination half-lives (t1/2) of 2.72 +/- 0.58 h (test 1), 2.39 +/- 0.37 h (test 2) and 2.63 +/- 0.66 h (reference) were determined. Both primary target parameters, AUC(0-infinity) and AUC(0-t) were tested parametrically by analysis of variance (ANOVA) and relative bioavailabilities were 98.0 +/- 16.2% (test 1) and 97.2 +/- 20.3% (test 2) for AUC(0-infinity), 97.5 +/- 16.3% (test 1) and 97.8 +/- 20.2% (test 2) for AUC(0-t). Bioequivalence between test and reference preparation was demonstrated for both parameters, AUC(0-infinity) and AUC(0-t). The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%. That means that the two test formulations are bioequivalent to the reference formulation for clindamycin.     

Determination of the transdermal bioavailability of a newly developed diclofenac sodium patch in comparison with a reference preparation

Two different transdermal diclofenac (CAS 15307-86-5) formulations (Olfen Patch 140 mg diclofenac sodium as test preparation and 180 mg diclofenac epolamine plaster, equivalent to 140 mg diclofenac sodium, as reference preparation) were investigated in 24 healthy male and female volunteers in order to compare the transdermal bioavailability between both treatments following topical multiple dose administration. Subjects were applied 2 plasters of test and reference formulation at a dose interval of 12 h for 4 consecutive days. Test and reference preparation were administered in randomised sequence at a marked spot at the left upper arm under non-fasting conditions. For determination of diclofenac concentrations, pre-dose (trough) values were taken during steady-state build-up and during the period of switch-over between both preparations on days 1-3 and 5-7. Blood samples for pharmacokinetic profiling were taken on days 4 and 8 at pre-defined time points up to 24 h following drug administration (after the 7th resp. 15th dose). Treatments were not separated by a wash-out phase. Considering the short half-life of diclofenac, it was appropriate that a switch-over design was chosen without wash-out periods between treatments. Diclofenac plasma concentrations were determined by means of a validated LC-MS/MS method (limit of detection: 0.06 ng/ml; lower limit of quantification: 0.15 ng/ml). For the test preparation, maximum plasma concentrations of 3.36 ng/ml (C(max, 0-12)), 3.73 ng/ml (C(max, 12-24)) and 3.84 ng/ml (C(max, 0-24)) as well as areas under the plasma concentration-time curve (AUC) of 31.11 ng x h/ml (AUC(0-12), 34.83 ng x h/ml (AUC(12.24)) and 65.94 ng x h/ml (AUC(0-24)) were determined. For the reference preparation, these values were 1.55 ng/ml (C(max, 0-12)), 1.45 ng/ml (C(max, 12-24) and 1.57 ng/ml (C(max, 0-24)) as well as 13.28 ng x h/ml (AUC(0-12)), 12.68 ng x h/ml (AUC(12-24)) and 25.96 ng x h/ml (AUC(0-24)). For the test preparation, peak-to-trough fluctuations (% PTF) of 34.78% (% PTF(0-12)), 38.50% (% PTF(12-24)) and 43.68% (% PTF(0-24)) were observed. Corresponding values for the reference preparation were 35.82% (% PTF(0-12), 31.36% (% PTF(12-24)) and 40.55% (% PTF(0-24)). In order to evaluate comparable bioavailability of both preparations, 90% confidence intervals of the test/reference ratios were determined. Thereby, for all dose intervals considered and all AUC parameters calculated, the extent of diclofenac absorption from the test preparation markedly exceeds those values obtained for the reference preparation. Likewise, maximum plasma concentrations, as a measure for the rate of absorption, were higher after the test preparation. With respect to peak-to-trough fluctuation of plasma diclofenac levels, both plaster preparations were comparable for the morning dose interval 0-12 h as well as for the 0-24 h period.     

细胞色素P450 CYP2C9*3对格列本脲和氯诺昔康中国人体药代动力学的影响

目的研究人体内细胞色素P450 2C9酶突变等位基因CYP2C9*3对格列本脲和氯诺昔康药代动力学的影响。方法采用PCR-RFLP方法对83名无血源关系的受试者进行CYP2C9*3等位基因的筛查，基因型为CYP2C9*1/*3(n=7)和*1/*1(n=11)的受试者分别参加了格列本脲和氯诺昔康的人体药代动力学试验。采用LC/MS/MS法分别测定受试者口服格列本脲(2.5 mg)和氯诺昔康(8 mg)后不同时刻血浆中格列本脲和氯诺昔康的浓度。结果两组受试者口服格列本脲后，CYP2C9*1/*3组AUC_0-∞显著增加，为CYP2C9*1/*1组的1.5倍，CL/F降低了40%；两组受试者口服氯诺昔康后，CYP2C9*1/*3组AUC_0-∞亦显著增加，为CYP2C9*1/*1组的2.2倍，CL/F降低了55%。结论CYP2C9酶的突变等位基因CYP2C9*3对格列本脲和氯诺昔康的药代动力学有显著性影响。     

Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women

The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.     

Effect of food on the pharmacokinetic profile of eslicarbazepine acetate (BIA 2-093)

OBJECTIVE: To investigate the effect of food on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel antagonist. MATERIAL AND METHODS: Single-centre, open-label, randomised, two-way crossover study in 12 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 14 days or more. In each of the study periods subjects were administered a single dose of eslicarbazepine acetate 800 mg following either a standard high-fat content meal or 10 hours of fasting. RESULTS: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (C(max)) in fed (test) and fasting (reference) conditions were, respectively, 12.8 +/- 1.8 microg/mL and 11.3 +/- 1.9 microg/mL, and the areas under the plasma concentration time curve from 0 to infinity (AUC(infinity)) were, respectively, 242.5 +/- 32.1 microg.h/mL and 243.6 +/- 31.1 microg.h/mL (arithmetic mean +/- SD). The point estimate (PE) and 90% confidence interval (90% CI) of the test/reference C(max )geometric mean ratio were 1.14 and 1.04, 1.25, respectively; for the AUC(infinity) ratio, the PE and 90% CI were 1.00 and 0.95, 1.04, respectively. Bioavailability of eslicarbazepine acetate administered in fed and fasting conditions was similar and bioequivalence is accepted for both AUC(infinity) and C(max) because the 90% CI lies within the acceptance range of 0.80-1.25. No statistically significant differences were found in time of occurrence of C(max). CONCLUSION: The presence of food had no significant effect on the pharmacokinetics of eslicarbazepine acetate and therefore this new voltage-gated sodium channel antagonist may be administered without regard to meals.     

Anidulafungin does not require dosage adjustment in subjects with varying degrees of hepatic or renal impairment

Two open-label studies assessed the effects of hepatic and renal impairment on anidulafungin pharmacokinetics. A single 50-mg dose was administered intravenously to subjects with varying degrees of hepatic or renal insufficiency or with end-stage renal disease; all were matched to normal healthy controls. Anidulafungin was well tolerated. AUC, CL, C(max), t(max), t(1/2), and V(ss) between renally impaired subjects and controls were not significantly different (P>.05), and no measurable amounts of drug were found in dialysate. The same pharmacokinetic parameters were also not affected (P>.05) by mild or moderate hepatic insufficiency, with respective mean AUCs of 50.6 +/- 11.7 microg x h/mL and 68.6 +/- 14.5 microg x h/mL, compared to 70.0 +/- 13.4 microg x h/mL in controls. Statistically significant decreases (P<05) of AUC (33% change) and C(max) (36% change) in severely hepatically impaired subjects compared to controls--most likely secondary to ascites and edema--were not clinically relevant. Anidulafungin can be safely administered to patients with any degree of hepatic or renal impairment without dosage adjustment and without regard to hemodialysis schedules.     

固相萃取结合HPLC-MS测定人血浆中奥曲肽的浓度及相对生物利用度固相萃取结合HPLC-MS测定人血浆中奥曲肽的浓度及相对生物利用度

目的建立人血浆中奥曲肽浓度的HPLC-MS测定法，研究国产奥曲肽注射剂的人体生物利用度。方法 血浆样品用HPL 1cc固相萃取小柱萃取，经Waters Xetrra C₁₈ MS分离后测定。18名健康志愿受试者采用随机交叉试验设计，分别im奥曲肽试验制剂和参比制剂200 μg，不同时间点采血，比较两者的生物利用度。结果线性范围0.5～40 μg·L^-1，方法回收率为97.1%～100.5%。日内、日间RSD分别为1.1%～1.6%，2.9%～4.8%。单剂量im奥曲肽200 μg后两种制剂的C_max分别为（19±10） μg·L^-1和（19±11） μg·L^-1，t_max分别为（0.50±0.15） h和（0.52±0.20） h；AUC_0～7h分别为（50±25） h·μg·L^-1和（50±25） h·μg·L^-1，t_1/2分别为(1.5±0.8) h 和(1.5±0.8) h。二者之间均无显著性差异，以进口奥曲肽为参比制剂，国产奥曲肽注射液的相对生物利用度为101%±10%。结论该方法灵敏、准确度高，可用于奥曲肽体内过程研究。两注射剂为生物等效性制剂。     

Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.     

Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in healthy volunteers. Three doses of either 750 mg or 1000 mg levofloxacin were administered intravenously to 4 healthy adult subjects (750 mg) to 20 healthy adult subjects divided into five groups of 4 subjects (1000 mg). Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Levofloxacin was measured in plasma, BAL fluid and alveolar cells (ACs) using a sensitive and specific combined high-performance liquid chromatographic tandem mass spectrometric technique (HPLC/MS/MS). Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. The maximum plasma drug concentration to minimum inhibitory concentration ratio (C(max)/MIC(90)) and the area under the drug concentration curve to minimum inhibitory concentration ratio (AUC/MIC(90)) during the dosing interval were calculated for potential respiratory pathogens with MIC(90) values from 0.03 microg/mL to 2 microg/mL. In the 1000 mg dose group, the C(max) (mean+/-standard deviation (S.D.)), AUC(0-8h) and half-life were: for plasma, 9.2+/-1.9 microg/mL, 103.6 microg h/mL and 7.45 h; for ELF, 25.8+/-7.9 microg/mL, 279.1 microg h/mL and 8.10h; and for ACs, 51.8+/-26.2 microg/mL, 507.5 microg h/mL and 14.32 h. In the 750 mg dose group, the C(max) values in plasma, ELF and ACs were 5.7+/-0.4, 28.0+/-23.6 and 34.2+/-18.7 microg/mL, respectively. Levofloxacin concentrations were significantly higher in ELF and ACs than in plasma at all time points. For pathogens commonly associated with community-acquired pneumonia, C(max)/MIC(90) ratios in ELF ranged from 12.9 for Mycoplasma pneumoniae to 859 for Haemophilus influenzae, and AUC/MIC(90) ratios ranged from 139 to 9303, respectively. The C(max)/MIC(90) ratios in ACs ranged from 25.9 for M. pneumoniae to 1727 for H. influenzae, and AUC/MIC(90) ratios ranged from 254 to 16917, respectively. The C(max)/MIC(90) and AUC/MIC(90) ratios provide a pharmacokinetic rationale for once-daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of community-acquired respiratory pathogens.     

A simple high-performance liquid chromatographic method for the determination of acyclovir in human plasma and application to a pharmacokinetic study

A rapid, simple and sensitive reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the measurement of acyclovir (CAS 59277-89-3) concentrations in human plasma and its use in bioavailability studies is evaluated. The method was linear in the concentration range of 0.05-4.0 microg/ml. The lower limit of quantification (LLOQ) was 0.05 microg/ml in 0.5 ml plasma sample. The intra- and inter-day relative standard deviations across three validation runs over the entire concentration range were less than 8.2%. This method was successfully applied for the evaluation of pharmacokinetic profiles of acyclovir capsule in 19 healthy volunteers. The main pharmacokinetic parameters obtained were: AUC(o-t) 6.50 +/- 1.47 and 7.13 +/- 1.44 microg x h/ml, AUC(0-infinity) 6.77 +/- 1.48 and 7.41 +/- 1.49 microg x h/ml, C(max) 2.27 +/- 0.57 and 2.27 +/- 0.62 microg/ml, t(1/2) 2.96 +/- 0.41 and 2.88 +/- 0.33 h, t(max) 0.8 +/- 0.3 and 1.0 +/- 0.5 h for test and reference formulations, respectively. No statistical differences were observed for C(max) and the area under the plasma concentration--time curve for acyclovir. 90% confidence limits calculated for C(max) and AUC from zero to infinity (AUC(0-infinity)) of acyclovir were included in the bioequivalence range (0.8-1.25 for AUC).     

Bioavailability of melatonin in humans after day-time administration of D(7) melatonin

Absolute bioavailability of the neurohormone melatonin (MLT) was studied in 12 young healthy volunteers (six males, six females) after administration at midday, on two separate occasions, of 23 microg by intravenous (i.v.) infusion and 250 microg by oral solution of D(7) MLT, a molecule in which seven deuterium atoms replace seven hydrogen atoms. Exogenous (D(7)) and endogenous (D(0)) MLT were quantified simultaneously but separately by a highly specific assay: gas chromatography/negative ion chemical ionization mass spectrometry, developed in our laboratory, which enabled us to go down to 0.5 pg/mL in plasma samples. After i.v. administration, the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) values were significantly different in male and female subjects, but there was no significant gender difference in total body clearance normalized to body weight: 1.27+/-0.20 L/h/kg and 1.18+/-0.22 L/h/kg for males and females, respectively. The apparent terminal half-life (t(1/2(z))) values were 36+/-2 and 41+/-10 min, respectively. After oral administration, pharmacokinetic parameters used to quantify bioavailability were near three-fold greater in female subjects than in males, with large inter-individual variations. The maximum plasma MLT concentration C(max)+/-S.D. was found at 243.7+/-124.6 pg/mL and 623.6+/-575.1 pg/mL for male and female subjects respectively, while the mean values for AUCs were 236+/-107 pg.h/mL and 701+/-645 pg.h/mL. The absolute bioavailability of MLT was from 1 to 37%: mean=8.6+/-3.9% and 16.8+/-12.7% for male and female subjects, respectively.     

Enhanced bioavailability of process-induced fast-dissolving ibuprofen cogranulated with beta-cyclodextrin

The objectives of this study were to evaluate the bioavailability of cogranulated and oven-dried ibuprofen (IBU) and beta-cyclodextrin (betaCD), in comparison to a physical mixture, and to examine the effect of endogenous bile on the bioavailability of the drug. In vitro dissolution studies were performed using USP type 2 apparatus. The granules and physical mixture were administered perorally in a crossover fashion, to male Wistar bile duct-nonligated rats. The granules were also perorally administered to bile duct-ligated rats. Blood samples were taken at different time intervals and the plasma analyzed for IBU. Dissolution of granules was faster than the physical mixture due to faster IBU-betaCD complex formation in solution from the former than the latter. The in vivo study showed that C(max), AUC(0-8), and the absolute bioavailability for the granules (49.0 microg/mL, 57.0 h x microg/mL and 80.6%, respectively) were almost one and half times that of the physical mixture (32.2 microg/mL, 38.4 h x microg/mL and 53.1%, respectively). However, in bile duct-ligated rats, lower C(max) and AUC(0-8) (15.9 microg/mL and 14.4 h x microg/mL, respectively) were obtained for the granules. Phase solubility study of IBU in an aqueous betaCD solution in the presence of the bile salt (sodium cholate), showed an increase in the solubility of IBU. Moreover, the stability constant value for the IBU-betaCD complex was also found to decrease as the sodium cholate concentration increased. These results indicated that the enhancement in the bioavailability of IBU was due to faster in-solution complex formation, and micelllar solubilization by the bile salt.     

Bioavailability of diclofenac potassium at low doses

AIM: Diclofenac-K has been recently launched at low oral doses in different countries for over-the-counter use. However, given the considerable first-pass metabolism of diclofenac, the degree of absorption of diclofenac-K at low doses remained to be determined. The aim of this study was to determine the bioavailability of low-dose diclofenac-K. METHODS: A randomized, three-way, cross-over study was performed in 10 subjects. Each received diclofenac-K, 22.5 mg via short-term i.v. infusion and orally at single doses of 12.5 mg and 25 mg. RESULTS: Mean (+/- SD) times to maximal plasma concentration (t(max)) of diclofenac were 0.48 +/- 0.28 h (12.5 mg) and 0.93 +/- 0.96 h (25 mg). The absolute bioavailability of diclofenac-K after oral administration did not differ significantly in the 12.5-mg and 25-mg dose group (63.1 +/- 12.6%vs. 65.1 +/- 19.4%, respectively). The 90% confidence intervals for the AUC(infinity) and AUC(t) ratios for the two oral regimes were 82.6, 103.4% (point estimate 92.4%) and 86.2, 112.9% (point estimate 98.6%), respectively. These values were within the acceptance criteria for bioequivalence (80-125%). CONCLUSIONS: Our data indicate that diclofenac-K is rapidly and well absorbed at low dose, and are consistent with a rapid onset of action of the drug. Abbreviations AUC, area under plasma concentration-time curve; C(max), peak plasma concentration; CI, confidence interval; COX, cyclooxygenase; D, dose; F, absolute bioavailability; t(max), time to reach C(max).     

Comparative bioavailability of two oral suspensions of naproxen sodium

The bioavailability of naproxen sodium (CAS 26159-34-2) after administration of two oral suspensions, reference or test (Pactens), was compared in 24 healthy subjects. The volunteers received an oral dose of 250 mg (10 ml) in two separate sessions under fasting conditions according to a randomized cross-over design and blood samples were obtained at selected times for a period of 72 h. Plasma samples were analyzed by a high-performance liquid chromatographic method for determination of naproxen. Individual plasma concentration against time curves were constructed and pharmacokinetic parameters were obtained by non-compartmental techniques. The parameters obtained (mean +/- S.E.M.) were: C(max) 43.93 +/- 1.83 and 44.91 +/- 2.15 microg/ml, t(max) 2.38 +/- 0.21 and 1.83 < or = 0.19 h, AUC(72 h) 721.73 +/- 18.47 and 722.55 +/- 19.07 microg x h/ml for reference and test formulations, respectively. Maximal concentration, AUC(72 h) and AUC(infinity). were log transformed and compared by analysis of variance and ratios; in addition, 90% confidence limits were obtained. As confidence limits were included in the 80-125% range and the probability of exceeding these intervals was always lower than 0.05, it is concluded that the formulations tested are bioequivalent.     

注射用灯盏花素脂质体在Beagle犬体内的药代动力学

目的制备灯盏花素脂质体，研究灯盏花素脂质体在Beagle犬体内的药代动力学。方法采用双周期交叉试验法，6只Beagle犬分别单剂量(以灯盏乙素计为28 mg/只)静脉注射自制灯盏花素脂质体和市售普通注射液，用反相高效液相色谱法测定不同时间血浆中灯盏乙素的浓度，采用3P97计算药代动力学参数，并进行统计学分析。结果脂质体和市售注射液的T_1/2α分别为(4.4±0.7) min和(1.8±1.3) min；T_1/2<>分别为(55±27) min和(28±23) min；V_c分别为(1 580±265) mL和(2 460±2 200) mL；CL_s分别为(88±10) mL·min^-1和(324±69) mL·min^-1； AUC_0-720分别为(363±42) μg·min·mL^-1和(102±19) μg·min·mL^-1。两种制剂的T_1/2α，CL_s及AUC_0-720经方差分析后均存在极显著或显著性差异。结论与市售普通注射液相比，灯盏花素脂质体Beagle犬静脉注射给药后，大大提高了血药浓度，显著改善了灯盏乙素原药的药代动力学性质，具有缓释作用。     

双氯芬酸钠迟效制剂的药动学

目的 :以双氯芬酸钠普通肠溶片 (R)为对照 ,比较国产双氯芬酸钠迟效制剂 (T)的相对生物利用度和药动学。方法 :采用双交叉、自身对照的方法 ,将 2 4名受试者分为 2组 ,单剂量组分别口服T和R各 10 0mg ;多剂量组 ,每日分别口服T和R各10 0mg ,共 4d。结果 :单剂量组T和R的Cmax,Tmax,T1/2 ,MRT ,AUC0～τ分别为 (115 6±s 36 1)和(3910± 96 8) μg·L- 1,(3.0± 1.0 )和 (2 .3± 0 .5 )h ,(6 .6± 2 .3)和 (2 .9± 1.5 )h ,(12 .3± 2 .3)和 (4.4±1.0 )h ,(92 37± 994 )和 (874 5± 12 16 ) μg·h·L- 1,T的F为 (10 7± 12 ) %。多剂量口服T和R的Cav,FI分别为 (343± 4 6 ) μg·L- 1和 (333± 6 4) μg·L- 1,(2 5 4± 82 ) %和 (40 4± 97) %。结论 :2种制剂口服吸收相似 ,迟效制剂具有峰谷浓度差异小 ,血药浓度波动幅度小等缓释药动学特征。     

Absorption characteristics of EC-MPS--an enteric-coated formulation of mycophenolic sodium

Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine. OBJECTIVE: Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine. METHODS: Study 1: The mean MPA AUC(0-t) was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 microg x h/ml). Mean absolute bioavailability was 0.71 +/- 0.21 (SD). Study 2: The AUC(0-t) and C(max) for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC(0-infinity) and C(max) for MPA glucuronide were proportional to dose administered. RESULTS AND CONCLUSIONS: In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 - 2,160 mg with no serious adverse events reported.