AUC 0-24h Research Articles

Improvement in oral bioavailability and dissolution of tanshinone IIA by preparation of solid dispersions with porous silica.

This study aims to evaluate the oral bioavailability and dissolution of tanshinone IIA (tanIIA) by preparation of solid dispersions (SDs) with porous silica. SDs of tanIIA were prepared using a solvent method. The physicochemical properties, dissolution property, drug stability and in-vivo performance of the SDs prepared were all evaluated. Compared with tanIIA alone and corresponding physical mixtures, tanIIA from SDs showed remarkably improved in-vitro dissolution rate. After forming the SDs, tanIIA changed into an amorphous state, which can infer from differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Fourier transform infrared spectroscopy (FTIR) also revealed the presence of interactions between tanIIA and porous silica in SDs. During the stability study, there is no significant decreasing in either the in-vitro dissolution or the drug content, which was observed following storage at room temperature for 12 months. The results of a pharmacokinetic study in rats showed the areas under the concentration-time curve from 0 h to 24 h (AUC0-24h ) for the SDs and tanIIA were 1019.87 ± 161.819 mg/h per litre and 343.70 ± 75.628 mg/h per litre, respectively. SDs with porous silica as carrier could achieve superior oral bioavailability by improving drug dissolution, whereas drug stability could be maintained.

Solid supersaturatable self-nanoemulsifying drug delivery systems for improved dissolution, absorption and pharmacodynamic effects of glipizide

The objective of this study was to prepare a solid supersaturatable self-nanoemulsifying drug delivery system (solid S-SNEDDS) to improve the dissolution, absorption and pharmacodynamic effects of a poorly water-soluble drug: glipizide. The liquid supersaturatable formulation (liquid S-SNEDDS) was prepared by adding a polymeric precipitation inhibitor (HPMC-E5 at 5% w/w) to a liquid SNEDDS. Dilution of the liquid S-SNEDDS generated a nanoemulsion with a mean droplet size of 28.0 nm. The liquid S-SNEDDS was transformed into a free-flowing powder (solid S-SNEDDS) by adsorption onto calcium carbonate and talc. The solid S-SNEDDS generated a higher glipizide concentration in comparison with the solid SNEDDS (without HPMC-E5) during an in-vitro supersaturation test. Moreover, glipizide precipitated in an amorphous form from the solid S-SNEDDS. SEM studies of solid S-SNEDDS indicated the existence of molecularly dissolved glipizide. The solid S-SNEDDS was found to be stable during accelerated stability studies. In-vivo pharmacokinetic studies showed a significant (p < 0.001) increase in Cmax (3.4-fold) and AUC0–12h (2.7-fold) of glipizide from solid S-SNEDDS as compared with the pure drug. Solid S-SNEDDS showed a significant (p < 0.001) decrease in the plasma glucose level by 1.3, 1.3, and 2.9-fold as compared with solid SNEDDS, the commercially available drug product and the pure drug, respectively.

Enantiospecific determination of naftopidil by RRLC–MS/MS reveals stereoselective pharmacokinetics and tissue distributions in rats

Naftopidil (NAF) is used as a racemate to treat benign prostatic hyperplasia (BPH) and to prevent prostate cancer. However, racemic NAF has low bioavailability; therefore, it is commonly administered at higher clinical dosages compared to other therapeutic BPH drugs. Differences in interactions between individual enantiomers and biological macromolecules may result in variations in pharmacokinetics and dispositions. This study aimed to investigate the pharmacokinetics, bioavailability and tissue distributions of NAF enantiomers in rats after intragastric administration of the individual enantiomers. A rapid and sensitive liquid chromatography coupled with triple–quadrupole mass spectrometric method (RRLC–MS/MS) was developed and validated for determination of NAF enantiomers in rat plasma, tissues, urine and feces. After intragastric administration, S(−)-NAF in plasma [maximum concentration (Cmax)=186.4ng/mL, area under the curve from 0h to 24h (AUC0–24h)=877.9ngh/mL] was significantly higher than that of R(+)-NAF (Cmax=133.2ng/mL, AUC0–24h=602.1ngh/mL). Moreover, S(−)-NAF bioavailability was twice that of R(+)-NAF. R(+)-NAF distributions in the prostate, liver, and kidney were significantly higher than S(−)-NAF distributions (R/S ratios of 3.16, 1.33, and 2.90, respectively). These data reveal the stereoselective pharmacokinetic profiles of the two enantiomers in rats.

Pharmacokinetics, tissue distribution and excretion of isoalantolactone and alantolactone in rats after oral administration of Radix Inulae extract.

Radix Inulae is endemic to China and has been used in traditional medicine to treat upper body pain, emesis and diarrhoea, and to eliminate parasites. Here, an UPLC-MS/MS method was developed and applied to study the pharmacokinetics, distribution and excretion of isoalantolactone and alantolactone, which are two main active sesquiterpene lactones in Radix Inulae, in Sprague-Dawley rats following oral administration of total Radix Inulae extract. Isoalantolactone, alantolactone and osthole (internal standard) were prepared using acetonitrile precipitation, and the separation of isoalantolactone and alantolactone was achieved by isocratic elution using water (containing 0.1% formic acid) and acetonitrile as the mobile phase using a ZORBAX Eclipse Plus C18 column. The total run time was 6.4 min. The present study showed poor absorption of isoalantolactone and alantolactone in vivo. The apparent Cmax, Tmax, T1/2 and total exposure (AUC0–12h) in rat plasma were 37.8 ng/mL, 120 min, 351.7 min and 6112.3 ng-min/mL for isoalantolactone and 25.9 ng/mL, 90 min, 321.0 min and 4918.9 ng-min/mL for alantolactone, respectively. It was shown that the highest concentration was achieved in the small intestine and feces clearance was shown to be the dominant elimination pathway of the lactones.

Improve bile duct-targeted drug delivery and therapeutic efficacy for cholangiocarcinoma by cucurbitacin B loaded phospholipid complex modified with berberine hydrochloride

In present study, a novel phospholipid complex loaded cucurbitacin B modified with berberine hydrochloride (CUB-PLC-BER) was prepared by a simple solvent evaporation method with the aim of improving bile duct-targeted drug delivery and therapeutic efficacy for cholangiocarcinoma (CC). The complex’s physicochemical properties were systemically investigated in terms of scanning electron microscopy (SEM), x-ray diffraction (XRD) and infrared absorption spectroscopy (IR). In vivo and in vitro antitumor studies, CUB-PLC-BER and the unmodified cucurbitacin B-phospholipid complex (CUB-PLC) presented stronger antitumor efficacy against human cholangiocarcinoma cells (QBC939 cells) than free cucurbitacin B (CUB), while phospholipids (PL) itself had no significant toxicity. Besides that, CUB-PLC showed the advantage over the free CUB and CUB-PLC-BER with regard to the inhibition of tumor growth in vivo antitumor study. Failure to establish the orthotopic CC model, the study attempted to measure the level of CUB in plasma and in bile to explore bile duct-targeted effect indirectly. In the pharmacokinetics study in rats, the average values of Cmax and AUC0-8h of CUB-PLC-BER group in rat bile were higher than those of CUB-PLC, while an opposite result was found in plasma. Meanwhile, the Cmax, AUC0–8h and AUC0–24h of CUB were the least both in plasma and in bile. The results indicated that the CUB-PLC-BER tended to provide a high and prolonged drug concentration to bile duct, and PL played a central role in internalizing CUB into cells to improve the water insoluble drug’s permeability, which was of great benefit to enhance the bioavailability of CUB and improve therapeutic efficacy of CC. These results elucidated the potential of CUB-PLC-BER as drug delivery system for improving bile duct-targeted and therapeutic efficacy for CC.

High Drug Payload 10-Hydroxycamptothecin Nanosuspensions Stabilized by Cholesterol-PEG: In Vitro and In Vivo Investigation.

The objective of this study was to evaluate the feasibility of producing 10-hydroxycamptothecin nanosuspensions with high drug payload and to then determine the in vitro and in vivo characteristics of these nanosuspensions. Using cholesterol-PEG600 as a stabilizer, 10-hydroxycamptothecin nanosuspensions were successfully prepared using a precipitation-combined high-pressure homogenization method. A satisfactory drug payload of 90.39% (w/w) was achieved. The obtained nanosuspensions were spherical, with a mean particle size of 115.0 ± 0.4 nm, and they were monodisperse with a polydispersity index of 0.134 ± 0.001. The 10-hydroxycamptothecin remained in the same crystalline form in both the nanosuspensions and the bulk powder. In vitro, the 10-hydroxycamptothecin nanosuspensions released the encapsulated drug with nearly zero-order kinetics, and the accumulative release reached 90% within 72 hours. In vitro cytotoxicity assay showed that the 1 0-hydroxycamptothecin nanosuspensions had significantly enhanced cytotoxicity against HepG2 cells compared to the commercially available 10-hydroxycamptothecin injections. The in vivo study with H22 tumor-bearing mice and intravenous injection of the drug showed that in contrast to the 10-hydroxycamptothecin injections, the 10-hydroxycamptothecin nanosuspensions exhibited significantly enhanced biodistribution, particularly in the lung (393.40-fold AUC(0-24h)), liver (192.35-fold AUC(0-24h)), spleen (141.67-fold AUC(0-24h)) and tumor (64.21-fold AUC(0-24h)). The 10-hydroxycamptothecin nanosuspensions also showed improved antitumor therapeutic efficacy over the injections (89.83% vs. 30.56%). This suggests that cholesterol-PEG600 may be an effective stabilizer for the preparation of hydrophobic drug nanosuspensions and that 10-hydroxycamptothecin nanosuspensions are a promising drug delivery system for tumor treatment.

Pharmacokinetic Properties and Tolerability of Rotigotine Transdermal Patch After Repeated-Dose Application in Healthy Korean Volunteers

PurposeRotigotine, a nonergolinic dopamine receptor agonist, is a once-daily transdermal patch developed for the treatment of Parkinson’s disease and restless legs syndrome. The objective of the present study was to determine the pharmacokinetic characteristics and tolerability of rotigotine transdermal patch after repeated-dose application in healthy male and female Korean subjects. MethodsIn this randomized, double-blind, placebo-controlled, repeated-dose study, subjects were randomly assigned to receive either rotigotine or placebo (ratio, 20 rotigotine to 4 placebo, per sex). Rotigotine patches were applied once daily at a dose of 2 mg/24 h on days 1 to 3, followed by 4 mg/24 h on days 4 to 6. Serial blood and urine samples were collected on days 1 to 9 for the determination of the concentrations of rotigotine and its metabolites. Tolerability was evaluated by adverse events determined using physical examination, including vital signs with orthostatic measurements; ECG; and clinical laboratory testing. FindingsA total of 48 healthy Korean subjects were enrolled (24 men, 24 women; mean age, 24 years). Approximately 50% of the total drug content was delivered within 24 hours. The mean plasma concentration of unconjugated rotigotine increased proportionally with dose. At the 2 mg/24 h dose at steady state, the geometric mean AUC0–24h and Cmax values of unconjugated rotigotine were 5.88 ng·h/mL and 0.347 ng/mL, respectively; at the 4 mg/24 h dose, the corresponding values were 13.74 ng·h/mL and 0.838 ng/mL. The mean t½ of rotigotine was 4.96 hours. At the 2 mg/24 h dose at steady state, the geometric mean AUC0–24h and Cmax values of total rotigotine were 14.02 ng·h/mL and 0.776 ng/mL; at the 4-mg/24 h dose, 32.38 ng·h/mL and 1.867 ng/mL. Common adverse events reported in the rotigotine-treated subjects included nausea (17 subjects, 42.5%), headache (11, 27.5%), and dizziness (9, 22.5%). No clinically significant changes in blood pressure, ECG, or laboratory values were observed. ImplicationsThe mean plasma exposures of unconjugated rotigotine increased proportionally with dose. Repeated daily application of the rotigotine patch was well tolerated in these healthy Korean volunteers. ClinicalTrials.gov identifier: NCT01964573.

A validated liquid chromatography-tandem mass spectrometry method for the determination of methyl gallate and pentagalloyl glucopyranose: application to pharmacokinetic studies.

Methyl gallate (MG) and pentagalloyl glucopyranose (PGG) are bioactive phenolic compounds that are widely distributed in herbs and plant foods. Their potential activities include anti-oxidant, anti-inflammatory, anti-cancer, anti-bacterial and anti-viral activities. However, knowledge concerning the pharmacokinetic characteristics of MG and PGG is limited. The purpose of this study was to develop a sensitive and reproducible ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to simultaneously quantify MG and PGG in rat blood samples. The linear response ranges for MG and PGG were 0.0195-20 and 0.0390-20 μM, respectively. The lower limit of quantification was 0.0195 μM for MG and 0.0390 μM for PGG. The intra- and inter-day variances were less than 15%, and accuracy was within 80-120%. This assay was successfully applied to pharmacokinetic studies in Sprague-Dawley rats after intraperitoneal administration of MG and PGG (20 mg/kg). The values of areas under the blood concentration time curves (AUC₀₋₂₄ h) for MG and PGG were 109.9 ± 73.40 and 38.78 ± 24.53 h*μM, respectively. The maximum blood concentrations (Cmax) of MG and PGG were 34.72 ± 17.32 and 6.39 ± 4.25 μM, respectively. The time required to reach the maximum concentration (Tmax) was 0.85 ± 0.70 h for both MG and PGG. The values of the elimination rate constant (Ke), elimination half-life (t1/2), volume of distribution (Vd), clearance (Cl) and mean resident time (MRTlast) were 0.056 ± 0.032 h(-1), 17.50 ± 12.25 h, 530.95 ± 247.54 L/kg, 159.91±76.05L/h/kg, 8.71 ± 2.53 h for MG and 0.023 ± 0.012 h(-1), 38.66 ± 22.89 h, 7838.89 ± 3474.72 L/kg, 30.98 ± 21.73 L/h/kg, 12.47 ± 2.77 h for PGG, respectively. In conclusion, a UPLC-MS/MS method was fully validated over a wide linear range and used to quantify the levels of MG and PGG in pharmacokinetic studies of MG and PGG in rats. The main advantages of this method are the use of small blood volumes (10 μL), rapid analysis (5 min) and excellent recoveries.

Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis

Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration–response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2 weeks of intensified treatment, surviving patients had significantly higher rifampicin plasma AUC0–6h, plasma Cmax and CSF Chighest. Additionally, patients had a 32–43% lower relative likelihood of dying with an interquartile range increase in rifampicin exposure. Moxifloxacin exposure did not show a clear relationship with survival. From exposure–response curves, a rifampicin plasma AUC0–6h of ∼70mg·h/L (AUC0–24h of ∼116mgh/L) and a Cmax of ∼22mg/L were deduced as minimum target values for treatment. A strong concentration–effect relationship was found, with higher rifampicin exposure leading to better TBM survival. The current treatment dose of rifampicin is suboptimal; higher doses of rifampicin should be evaluated.

Pharmacokinetic drug-drug interaction study between raltegravir and citalopram.

Depression is the most common mental health disorder among HIV-infected patients. When treating HIV-infected patients with a selective serotonin reuptake inhibitor (SSRI), potential drug-drug interactions with antiretroviral agents have to be taken into account. We investigated the two-way pharmacokinetic drug-drug interaction and tolerability of concomitant administration of the SSRI citalopram and the HIV-1 integrase inhibitor raltegravir in healthy volunteers. An open-label, crossover, two-period trial was conducted in 24 healthy volunteers. Subjects received the following treatments: citalopram 20 mg once daily for 2 weeks followed by the combination with raltegravir 400 mg twice daily for 5 days and after a washout period raltegravir 400 mg twice daily for 5 days. Intensive steady-state pharmacokinetic blood sampling was performed. Geometric mean ratios (GMRs) of the combination versus the reference treatment and 90% CIs were calculated for the area under the plasma concentration-time curve (AUC). CYP2C19 genotyping was performed because it influences N-demethylation of citalopram to desmethylcitalopram. A total of 22 healthy volunteers completed the trial. GMRs (90% CI) were 1.00 (0.98, 1.03) for citalopram AUC0-24 h, 0.99 (0.88, 1.12) for desmethylcitalopram AUC0-24 h and 0.77 (0.50, 1.19) for raltegravir AUC0-12 h. Raltegravir plasma concentration 12 h after intake (C12 h) did not change with concomitant use of citalopram. Within each CYP2C19 phenotype subgroup the citalopram metabolite-to-parent ratio, which is a measure for metabolic enzyme activity, was not influenced by concomitant raltegravir use. Raltegravir does not influence the pharmacokinetics of citalopram and desmethylcitalopram. Citalopram did not change the pharmacokinetics of raltegravir in a clinically meaningful way. The combination was well tolerated and can be administered without dose adjustments. ClinicalTrials.gov NCT01978782.

Once-daily tiotropium Respimat® 5 μg is an efficacious 24-h bronchodilator in adults with symptomatic asthma

Once-daily tiotropium Respimat(®) 5 μg is an efficacious add-on therapy to inhaled corticosteroids (ICS) with or without long-acting β2-agonists in patients with symptomatic asthma. The objective of this study was to investigate whether the dosing regimen of tiotropium (once- versus twice-daily), delivered via the Respimat(®) SoftMist™ inhaler, affected 24-h bronchodilator efficacy and safety versus placebo Respimat(®) in patients with asthma who were symptomatic despite medium-dose ICS therapy. A randomised, double-blind, placebo-controlled, crossover study with 4-week treatment periods of tiotropium 5 μg (once-daily, evening) and 2.5 μg (twice-daily, morning and evening). The primary efficacy end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC)(0-24h) at the end of each treatment period. Secondary end points included peak forced expiratory volume in 1 s measured within 24 h of the last evening inhalation (peak FEV1(0-24h)), trough FEV1 measured prior to evening dosing, morning and evening peak expiratory flow (PEFam and PEFpm) and pharmacokinetic assessments. 94 patients were randomised (mean age 44.3 years; mean asthma duration 21.3 years) and 89 (94.7%) completed the study. Significant and comparable bronchodilation was achieved over a 24-h period with both tiotropium dosing regimens. FEV1 AUC(0-24h) response (mean ± standard error) was significantly greater with both tiotropium dosing regimens (once-daily 5 μg: 158 ± 24 mL; twice-daily 2.5 μg; 149 ± 24 mL; both p < 0.01) when compared with placebo. Improvements in peak FEV1(0-24h), trough FEV1 and pre-dose PEFam/pm with both dosing regimens versus placebo were statistically significant (all p < 0.01), with no statistically significant differences between the tiotropium treatment regimens. Total systemic exposure and tolerability were comparable between treatment regimens. Lung function improvements with tiotropium Respimat(®) add-on to medium-dose ICS were sustained and similar for once-daily 5 μg and twice-daily 2.5 μg, supporting tiotropium Respimat(®) 5 μg as a once-daily bronchodilator that provides efficacy over the whole 24-h dosing interval in patients with symptomatic asthma. ClinicalTrials.gov identifier: NCT01152450.

Pharmacokinetics and pharmacodynamics of insulin glargine given in the evening as compared with in the morning in type 2 diabetes.

To compare pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration. Ten T2DM insulin-treated persons were studied during 24-h euglycemic glucose clamp, after glargine injection (0.4 units/kg s.c.), either in the evening (2200 h) or the morning (1000 h). The 24-h glucose infusion rate area under the curve (AUC0-24h) was similar in the evening and morning studies (1,058 ± 571 and 995 ± 691 mg/kg × 24 h, P = 0.503), but the first 12 h (AUC0-12h) was lower with evening versus morning glargine (357 ± 244 vs. 593 ± 374 mg/kg × 12 h, P = 0.004), whereas the opposite occurred for the second 12 h (AUC12-24h 700 ± 396 vs. 403 ± 343 mg/kg × 24 h, P = 0.002). The glucose infusion rate differences were totally accounted for by different rates of endogenous glucose production, not utilization. Plasma insulin and C-peptide levels did not differ in evening versus morning studies. Plasma glucagon levels (AUC0-24h 1,533 ± 656 vs. 1,120 ± 344 ng/L/h, P = 0.027) and lipolysis (free fatty acid AUC0-24h 7.5 ± 1.6 vs. 8.9 ± 1.9 mmol/L/h, P = 0.005; β-OH-butyrate AUC0-24h 6.8 ± 4.7 vs. 17.0 ± 11.9 mmol/L/h, P = 0.005; glycerol, P < 0.020) were overall more suppressed after evening versus morning glargine administration. The PD of insulin glargine differs depending on time of administration. With morning administration insulin activity is greater in the first 0-12 h, while with evening administration the activity is greater in the 12-24 h period following dosing. However, glargine PK and plasma C-peptide levels were similar, as well as glargine PD when analyzed by 24-h clock time independent of the time of administration. Thus, the results reflect the impact of circadian changes in insulin sensitivity in T2DM (lower in the night-early morning vs. afternoon hours) rather than glargine per se.

Effect of HIV Infection and Menopause Status on Raltegravir Pharmacokinetics in the Blood and Genital Tract

This study describes first dose and steady state pharmacokinetics of raltegravir (RAL) in cervicovaginal fluid (CVF) and blood plasma (BP). Three cohorts of women were enrolled sequentially in a single-site, open-label pharmacokinetic study of oral raltegravir 400 mg twice daily: HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women. BP and CVF were collected over 12 h after a single observed dose and at steady state. RAL concentrations were measured by HPLC-MS methods. Data are expressed as median (IQR). The ANOVA rank-sum test was used to evaluate between-group differences in steady state raltegravir exposure (area under the concentration-time curve over the 12-h dosing interval [AUC0-12 h]). First dose pharmacokinetics were obtained in HIV-negative premenopausal women and HIV-infected post-menopausal women only. The median (IQR) BP AUC0-12 h was 3,099 (985-5,959) and 4,239 (2,781-13,695) ng•h/ml and the median (IQR) CVF AUC0-12 h was 1,720 (305-5,288) and 13,797 (11,066-19,563) ng•h/ml for HIV-negative premenopausal and HIV-infected post-menopausal women, respectively. All cohorts contributed to steady-state pharmacokinetic profiles. Median (IQR) BP AUC0-12 h did not differ between the groups: 8,436 (3,080-10,111), 5,761 (1,801-10,095) and 6,180 (5,295-8,282) ng•h/ml in HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women, respectively. There was a trend for lower CVF AUC0-12 h among HIV-negative women 3,164 (1,156-9,540) compared to 11,465 (9,725-17,138) and 9,568 (4,271-24,306) ng•h/ml HIV-infected premenopausal and HIV-infected post-menopausal women, respectively, but this was not statistically significant (P=0.08). HIV-negative premenopausal women had a median (IQR) CVF:BP AUC0-12 h ratio of 0.46 (0.2-1.1), whereas HIV-infected premenopausal and post-menopausal women had median (IQR) CVF:BP AUC0-12 h ratio of 3.9 (1.2-6.7) and 1.4 (0.7-4.3), respectively. This is the first study to investigate RAL exposure in BP and CVF in premenopausal HIV-negative and pre- and post-menopausal HIV-infected women. These data indicate HIV and menopausal status may influence antiretroviral distribution into the female genital tract.

Soluplus® based 9-nitrocamptothecin solid dispersion for peroral administration: Preparation, characterization, in vitro and in vivo evaluation

Our study aimed to develop an amorphous 9-nitrocamptothecin solid dispersion (9-NC-SD) using polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) for improving its oral bioavailability and antitumor efficacy in vivo. Freeze-dried 9-NC-SD with an optimized drug/polymer ratio at 1:15 (w/w) was characterized by powder X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The amorphous form of 9-NC was obtained by freeze-drying and the aqueous solubility of 9-NC was increased to 1.42mg/mL. Upon dilution, 9-NC-SD was proven to form micellar structures with an average size distribution around 58nm±5nm (PDI=0.107±0.016). Moreover, 9-NC-SD showed significantly increased intracellular uptake efficiency in Caco-2 cells compared to free 9-NC. Furthermore, the AUC0–8h of 9-NC-SD following oral administration showed a 2.68-fold increase in the lactone form of 9-NC compared to that of free 9-NC in Sprague-Dawley rats. The 9-NC-SD did not show obvious inflammatory responses and gastrointestinal toxicity following oral administration as demonstrated by the histological analysis of the rat intestinal sections. Thus, 9-NC-SD represents a promising approach for improving the solubility and oral bioavailability of drugs with poor solubility.

Self-micro emulsifying formulation improved intestinal absorption and oral bioavailability of bakuchiol.

Bakuchiol (BAK), isolated from the seeds of Psoralea corylifolia L., recently presents a variety of pharmacologic activities. However, the poor oral bioavailability limits its further development and clinical use. The purpose of this study was to establish a self-microemulsifying (SME) formulation for oral delivery improvement of BAK. The optimized liquid SME formulation was comprised of BAK (40%), Cremophor RH 40 (30%) and Labrasol (30%). The emulsion droplets were spherical in shape, and particle size and zeta potential were determined. The in vitro dissolution test of BAK-SME formulation illustrated faster dissolution rate than the bulk drug. The permeabilities of 40μgmL-1 BAK-SME formulation in rat intestinal segments of duodenum, jejunum, ileum and colon were 30.91×10-3, 23.61×10-3, 29.43×10-3 and 23.62×10-3 cmmin-1, respectively, exhibiting 3.99 times in duodenum, 2.59 times in ileum and 2.31 times in colon greater than BAK perfusate. The oral bioavailability of BAK-SME formulation at a dose of 150mgkg-1 was determined in rats. The Cmax and the AUC(0-24h) were 515.4ngmL-1 and 4,327.2hngmL-1, respectively, which were 1.90 fold and 1.73 fold greater than the value of BAK suspension. All these results clearly stated that BAK-SME formulation performed well-improvement on oral bioavailability of BAK.

Plasma and cerebrospinal fluid concentrations of linezolid in neurosurgical critically ill patients with proven or suspected central nervous system infections

Linezolid is a valuable treatment option for central nervous system (CNS) infections caused by multidrug-resistant Gram-positive micro-organisms. Data regarding its penetration into the CNS have shown wide variability. The aim of this study was to describe the population pharmacokinetics of linezolid in plasma and cerebrospinal fluid (CSF) in critically ill patients with external CSF drainage and proven or suspected CNS infections. This was an observational pharmacokinetic (PK) study in 11 critically ill patients with proven or suspected CNS infection receiving linezolid. Serial blood and CSF samples were taken and were subject to population PK analysis. The median (interquartile range) of AUC0–12h was 47.6 (17.9–58.6)mgh/L in plasma and 21.1 (18.8–30.4)mgh/L in CSF, with a median CSF/plasma ratio of 0.77. At pre-dose at steady state, a strong positive correlation was observed between linezolid concentrations in CSF and plasma (Spearman's rho=0.758; P=0.011). For a minimum inhibitory concentration (MIC) of 2mg/L, the median AUC0–24h/MIC values in plasma and CSF were <80 in all patients. A three-compartment linear model was found to be most appropriate. The mean value for linezolid clearance was 16.6L/h and mean volume of distribution was 101.3L. No covariate relationships could be supported on any of the parameters. Linezolid demonstrated good penetration into the CNS but high interindividual PK variability. Administration of higher than standard doses of linezolid and therapeutic drug monitoring should therefore be considered as options to optimise linezolid dosing in critically ill patients with CNS infections.

Pharmacokinetic Parameters of Ciprofloxacin in Bangladeshi Volunteers: A Preliminary Evaluation

The present study has attempted to establish a High-performance liquid chromatography (HPLC) method to determine ciprofloxacin in plasma, in order to evaluate the bioavailability of ciprofloxacin. In this study, initially 8 (eight) Bangladeshi Bangalee healthy male volunteers and 7 (seven) Bangladeshi Tribal healthy male volunteers received 500 mg tablet of pioneer brand of ciprofloxacin in oral route. Blood samples were collected at 0, 30, 60, 120, 180, 360, 540 and 720 minutes after drug administration. After 1 week of washout period, same volunteers of two groups received 200 mg injection of pioneer brand of ciprofloxacin in intravenous route. HPLC with ultraviolet detection was used to quantify plasma ciprofloxacin concentrations. In case of oral route, AUC0–12h, Cmax, Tmax and T1/2 values for Bangladeshi Bangalee and Tribal healthy volunteers were 545.53 ± 32.35 &amp; 655.74 ± 16.57 ?g min/mL, 2.19 ± 0.16 &amp; 2.49 ± 0.20 ?g/mL, 75.00 ± 27.77 &amp; 94.29 ± 32.07 min and 241.96 ± 13.53 &amp; 242.02 ± 19.88 min respectively. In case of intravenous route, the AUC0–12h, Cmax, Tmax and T1/2 values for Bangladeshi Bangalee and Tribal healthy volunteers were 344.07 ± 29.31 &amp; 343.31 ± 25.34 ?g min/mL, 2.47 ± 0.17 &amp; 2.46 ± 0.18 ?g/mL, 30.00 ± 0.00 &amp; 30.0 ± 0.0 min and 278.16 ± 1.74 &amp; 272.74 ± 4.42 min respectively and the difference between these two groups of volunteers was not significant. The difference in AUC0–12h, Cmax, Tmax and T1/2 values between these two groups of volunteers was significant. The mean percent absolute bioavailability in Bangladeshi Bangalee and Tribal healthy volunteers was 64.04 ± 3.21 and 76.81 ± 6.71 respectively. In conclusion, pharmacokinetic parameters of ciprofloxacin significantly varied among Bangladeshi Bangalee and Bangladeshi Tribal healthy volunteers indicating necessity of further study on population pharmacokinetic in these groups of people. DOI: http://dx.doi.org/10.3329/bjpp.v27i1-2.20066 Bangladesh J Physiol Pharmacol 2011;27(1&amp;2):1-8.

Pharmacokinetic parameters of Amoxicillin in Bangladeshi volunteers: a preliminary evaluation

The present study was designed to get preliminary idea about the pharmacokinetic behavior of the Bangladeshi population through estimating plasma amoxicillin concentration by High-Performance Liquid Chromatography (HPLC) with ultraviolet detection. In this study, Bangladeshi healthy volunteers were divided in two groups, 8 Bangladeshi Bangalee and 7 Bangladeshi Tribal male healthy volunteers. Both the groups received 500 mg of amoxicillin in oral route and blood samples were collected at 0, 30, 60, 120, 180, 360 and 480 minutes after drug administration. After 1 week of washout period, same volunteers of two groups received 500 mg of amoxicillin in intravenous route. In case of oral route, the Cmax, AUC0–8h, Tmax and T1/2 values for Bangladeshi Bangalee and Tribal healthy volunteers were 6.78 ± 1.20 &amp; 9.10 ± 1.34 ìg/mL, 1290.13 ± 158.39 &amp; 1766.06 ± 188.37 ìg min/mL, 82.50 ± 32.05 &amp; 102.86 ± 29.28 min and 96.05 ± 3.80 &amp; 88.15 ± 5.33 min respectively. The difference in Cmax, AUC0–8h and T1/2 values between these two groups of volunteers was significant (p&lt;0.01, p&lt;0.001 and p&lt;0.01 respectively). However, the difference in Tmax was not significant (p&gt;0.05). In case of intravenous route, the C30 min and AUC0–8h values for Bangladeshi Bangalee and Tribal healthy volunteers were 17.88 ± 1.14 &amp; 18.58 ± 0.71 ìg/mL, 2297.96 ± 222.49 &amp; 2376.41 ± 149.99 ìg min/mL respectively and the difference was not significant (p&gt;0.05). The T1/2 for Bangladeshi Bangalee and Tribal healthy volunteers were 97.50 ± 3.33 &amp; 94.40 ± 2.33 min respectively and the difference was significant (p&lt;0.05). The Mean Percent Absolute Bioavailability in Bangladeshi Bangalee and Tribal healthy volunteers was 56.76 ± 5.39 and 74.17 ± 3.90 respectively and the difference was highly significant (p&lt;0.001). The study concluded that the pharmacokinetic parameters of amoxicillin significantly varied among Bangladeshi Bangalee and Bangladeshi Tribal healthy volunteers indicating necessity of further study on population pharmacokinetic to formulate tailor-made drug therapy in these groups of people. http://dx.doi.org/10.3329/bjpp.v26i1-2.19958 Bangladesh J Physiol Pharmacol 2010; 26(1&amp;2) : 1-9

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study

AimsIpragliflozin is a novel and highly selective sodium–glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM. MethodsIn this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50mg or 100mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days −1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0–3h (AUC0–3h) and 0–24h (AUC0–24h). Pharmacokinetic characteristics included AUC0–24h, maximum ipragliflozin concentration (Cmax), and time to maximum plasma ipragliflozin concentration (tmax). ResultsThirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC0–3h and AUC0–24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC0–24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0–24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group. ConclusionsIpragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.

Study on intralymphatic-targeted hyaluronic acid-modified nanoliposome: Influence of formulation factors on the lymphatic targeting

In this study, hyaluronic acid-modified docetaxel-loaded liposomes were prepared to evaluate the lymphatic targeting after subcutaneous administration, and formulation factors affecting the lymphatic targeting were examined, including free hyaluronic acid, molecular weight, hyaluronic acid-density and particle diameter. The high molecular weight hyaluronic acid-modified docetaxel-loaded liposomes (HA-LPs) and low molecular weight hyaluronic acid-modified docetaxel-loaded liposomes (LMWHA-LPs) were prepared via electrostatic attraction. The physicochemical properties and in vitro drug release were evaluated. The lymphatic drainage and the lymph node uptake were investigated by pharmacokinetics and distribution recovery of docetaxel in lymph nodes, injection site and plasma. The lymphatic targeting ability of optimized Cy7-loaded LMWHA-LPs (LMWHA-LPs/Cy7) was evaluated by near-infrared fluorescence imaging technique. The result showed that HA-LPs and LMWHA-LPs with suitable and stable physicochemical properties could be used for in vivo lymphatic targeting studies. Hyaluronic acid-modified liposome significantly increased the docetaxel recovery in lymph nodes, and displayed higher AUC(0-24h) and longer retention time compared to unmodified liposomes in vivo. In contrast, the presence of free hyaluronic acid hindered the lymphatic drainage and increased the plasma-drug concentration. Importantly, LMWHA-modification improved lymphatic drainage and lymph node uptake of liposomes compared with HA-modification. And Lymph node uptake of LMWHA-LPs depended mainly on LMWHA-density instead of particle size. The results of in vivo imaging showed that LMWHA-LPs/Cy7 significantly located in the lymphatic system. And both DTX-loaded and Cy7-loaded LMWHA-LPs had similar and stable lymphatic target level. Our investigation showed that LMWHA-LPs were a highly promising lymphatic targeting carrier for chemotherapy drugs and diagnostic fluorescence agents.