Transdermal delivery of (-)-epigallocatechin-3-gallate, a green tea polyphenol, in mice

Epigallocatechin-3-gallate (EGCG) is the most studied catechin in green tea (Camellia sinensis). EGCG and green tea are cancer preventive in many animal models, and numerous mechanisms have been proposed in cell lines. EGCG is poorly bioavailable in man and rodents. We hypothesized that transdermal delivery of EGCG could result in improved bioavailability. Following application of EGCG transdermal gel (50 mg kg(-1), t.d.) to SKH-1 mice, EGCG was observed in the epidermis (1365.7-121.0 ng g(-1)) and dermis (411.2-42.6 ng g(-1)). The maximum plasma concentration (Cmax) of EGCG was 44.5 ng mL(-1). The t(1/2) (94.4 h) and AUC(0-->24 h) (881.5 ng mL(-1) h) of EGCG were greater than values previously reported for oral EGCG. The t(1/2) and area under the concentration-time curve up to 24 h (AUC(0-->24 h)) in the liver, small intestine and colon were 21.3-74.6 h and 715-2802 ng g(-1)h, respectively. Stability studies showed that the transdermal formulation was stable at 4 degrees C and had a half-life (t(1/2)) of 47.1 and 20.2 h at 25 degrees C and 37 degrees C, respectively. These data indicate that transdermal EGCG is useful for delivering prolonged levels of EGCG to plasma and tissues, and may provide an alternative to tea consumption as a dosage form of EGCG.     

9-nitrocamptothecin polymeric nanoparticles: cytotoxicity and pharmacokinetic studies of lactone and total forms of drug in rats

The objective of this study was to evaluate the cytotoxicity and pharmacokinetics of total and lactone forms of 9-nitrocamptothecin (9-NC), an effective antineoplastic drug, after intravenous injection of drug incorporated into poly (DL-lactic-glycolic acid) nanoparticles (NPs). Drug-loaded NPs (9-NC.NP) were prepared by the nanoprecipitation method and examined for particle characteristics and in-vitro release in phosphate buffered saline. The best formulation showed a narrow size with an average diameter of 207+/-26 nm and a drug loading of more than 33.5%. The drug release profile showed a sustained 9-NC release up to 160 h. For a pharmacokinetic study, the concentration of 9-NC as the lactone form (9-NC.lac) and as the total of the lactone and carboxylate forms (9-NC.tot) in plasma was determined by using reverse-phase high performance liquid chromatography after intravenous administration of 9-NC.NP and a control solution to cannulated Wistar rats. In-vitro cytotoxic activity of 9-NC.NP and control solution was evaluated on the human ovarian cancer cell line (A2780sn) by MTT cell cytotoxicity assay. Results of in-vivo studies showed that NP encapsulation markedly increased the plasma concentration of both lactone and total forms of 9-NC compared with free drug. In comparison with free drug, NPs resulted in 3.63-fold and 5.40-fold increases in area under the plasma concentration-versus-time curve (AUC(0-infinity)) for lactone and total forms of 9-NC, respectively. The values of mean residence time and elimination half-life (T(1/2)) were also significantly higher for NPs than for free drug. The in-vitro cytotoxicity study revealed that the IC50 value of NPs decreased 10-fold compared with the drug solution. Prepared NPs described here were considered potentially useful in both stabilizing and delivering 9-NC and enhancing the efficacy of this drug for cancer treatment for which high drug retention in the body, protection from the drug-active lactone form, and gradual drug release appeared to be related.     

Gastrointestinal absorption of a new reversible proton pump inhibitor, YJA-20379-8, and its pharmacokinetics after oral administration in acetic acid-induced gastric ulcer in rats.

The absorption of YJA-20379-8 (3-butyryl-4-[5-(R)-(+)-methylbenzylamino]-8-ethoxy-1,7-naphthyrid ine) from various rat gastrointestinal segments was evaluated using in-situ closed-loops. The pharmacokinetics of the drug were also evaluated after oral administration to rats with acetic acid-induced gastric ulcer (AIURs). The concentrations of YJA-20379-8 in the biological samples were analyzed by HPLC. The absorption of YJA-20379-8 from stomach and jejunum was fast, but approximately 50% of the drug was recovered from each segment at 24 h. The total areas under the plasma concentration-time curves from time zero to 24h (AUC(0-24h)) were 161, 392, 233, 365, and 226 microg min mL(-1) for stomach, duodenum, jejunum, ileum, and colon, respectively. After oral administration of the drug, the plasma concentrations and the resultant AUC (0- 12h) were not significantly different between control and AIURs. The detection limits of YJA-20379-8 in human plasma and urine were 50 and 100 ng mL(-1), respectively. The results suggest that modification of the oral dose of YJA-20379-8 may not be required in gastric ulcer patients if the present rat pharmacokinetic data could be extrapolated to man.     

Thiolated chitosan nanoparticles for the nasal administration of leuprolide: bioavailability and pharmacokinetic characterization

The purpose of this study was to develop thiolated nanoparticles to enhance the bioavailability for the nasal application of leuprolide. Thiolated chitosan-thioglycolic acid (chitosan-TGA) and unmodified chitosan nanoparticles (NPs) were developed via ionic gelation with tripolyphosphate (TPP). Leuprolide was incorporated during the formulation process of NPs. The thiolated (chitosan-TGA) NPs had a mean size of 252 ± 82 nm, a zeta potential of +10.9 ± 4 mV, and payload of leuprolide was 12 ± 2.8. Sustained release of leuprolide from thiolated NPs was demonstrated over 6h, which might be attributed to inter- and/or intramolecular disulfide formation within the NPs network. Ciliary beat frequency (CBF) study demonstrated that thiolated NPs can be considered as suitable additives for nasal drug delivery systems. Compared to leuprolide solution, unmodified NPs and thiolated NPs provoked increased leuprolide transport through porcine nasal mucosa by 2.0 and 5.2 folds, respectively. The results of a pharmacokinetic study in male Sprague-Dawley rats showed improved transport of leuprolide from thiolated NPs as compared to leuprolide solution. Thiolated NPs had a 6.9-fold increase in area under the curve, more than 4-fold increase in elimination half-life, and a ～3.8-fold increase in maximum plasma concentration compared to nasal solution alone. The relative nasal bioavailability (versus s.c. injection) of leuprolide thiolated NPs calculated on the basis of AUC((0-6)) was about 19.6% as compared to leuprolide solution 2.8%. The enhanced bioavailability of leuprolide is likely due to facilitated transport by thiolated NPs rather than improved release.     

Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man--no evidence of enantioselective lung metabolism

Aims To establish whether enantioselective metabolism of racemic (rac )-salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes. Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 microg) with or without oral charcoal and intravenous (500 microg) rac-salbutamol. Systemic exposure (plasma AUC(0,infinity) and urinary excretion (Au24h ) of both enantiomers were calculated, and relative exposure to (R)-salbutamol both in plasma (AUC(R)-/AUC(S)- ) and urine (Au(R)-/Au(S)- ) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route. Results AUC(R)-/AUC(S)- [geometric mean (95% CI)] was similar following the intravenous [0.32 (0.28, 0.36)] and inhaled with charcoal rates [0.29 (0.24, 0.36); P=0.046], but was far lower following oral dosing [0.05 (0.03, 0.07); P<0.001]. Similar results were found when relative exposure was analysed using Au24h. Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)- and (S)-enantiomers are present in similar quantities in the airways following inhaled rac-salbutamol.     

Rapid in vivo oral screening in rats: Reliability, acceptance criteria, and filtering efficiency

The reliability and acceptance criteria of rapid oral exposure screening were evaluated by pharmacokinetic simulations and by comparing oral exposure of 100 proprietary compounds from 15 therapeutic programs obtained at different times by cassette accelerated rapid rat screen (CARRS) and conventional pharmacokinetic (full-PK) procedures. Once acceptance criteria were established, the filtering efficiency (discard rate) was assessed with a larger data set of 5289 compounds tested by CARRS only. These evaluations indicated that area under the concentration-time curve during the first 6 hours (AUC(6h)) captured >50% of AUC(infinity) for most (71%) of the compounds and AUC(6h) from CARRS is comparable to AUC(6h) from full-PK in categorizing oral exposure as low, moderate, or high; therefore, the truncated AUC(6h) derived from pooled plasma samples is suitable for oral exposure screening. The CARRS profiles did not provide reliable half-life estimates; however, compounds with substantial AUC beyond 6 hours can be identified when (C(6h)/Cmax x 100%) exceeds 80%. Of interest, both the observed data and the simulated data indicated that AUC(6h) can be estimated using a single time point plasma concentration at 3 hours. The relationship between the maximum bioavailability and AUC(infinity) over a range of clearance values was simulated. A threshold AUC (500 h*ng/mL) at the routine screening dose of 10 mg/kg was established below which a compound can be discarded. Examination of screening results for 5289 compounds evaluated over the last few years in our laboratory indicated that CARRS had a filtering efficiency of 50%, suggesting that this criterion provides a useful decision gate to avoid wasting the drug discovery resources on nonviable candidates.     

Absorption of rivastigmine from different regions of the gastrointestinal tract in humans

The objective of this study was to evaluate the rate and extent of absorption and metabolism of rivastigmine (Exelon), ENA 713) after site-specific delivery of the drug in the gastrointestinal (GI) tract using a naso-intestinal intubation technique. Healthy adult subjects (n = 7) received, on four separate occasions, a 3-mg dose of a rivastigmine solution (2 mg/mL) orally and via a naso-intestinal tube to three GI sites (jejunum, ileum, and ascending colon). On each of the 3 treatment days for regional GI dosing, the tube was progressed to each of the three GI sites, which was determined by a radiographical technique prior to dosing. On the fourth day, following tube withdrawal, the subject received a 3-mg oral dose of a rivastigmine solution. Plasma samples were obtained at different multiple time points, and the plasma concentrations of rivastigmine and its metabolite, NAP 226-90, were determined using a gas chromatography/mass spectrometry (GC/MS) method. Rivastigmine was rapidly absorbed following both oral administration and site-specific delivery to different regions of the GI tract (jejunum, ileum, and ascending colon). Compared with oral administration (AUV(0- infinity ) = 21 ng*h/mL, C(max) = 12.8 ng/mL, and t(max) = 0.87 h), delivery of the drug directly into the ileum, jejunum, and ascending colon did not change the extent of absorption, but the time to peak concentration appeared to be smaller (mean t(max) ranged from 0.4-0.6 h, with no change in C(max)). The relative bioavailability of rivastigmine from all three regions of the GI tract was comparable to that following oral administration. The metabolite levels (AUC, C(max)) were also similar among the three different regions of the GI tract when compared to the oral dose. It was concluded that rivastigmine is rapidly and equally well absorbed following an oral dose and after specific delivery to different regions of the small intestine and ascending colon. GI metabolism of rivastigmine to its major metabolite, NAP 226-90, occurs to a similar extent in different segments of the GI tract.     

Design and evaluation of novel pH-sensitive chitosan nanoparticles for oral insulin delivery

Chitosan nanoparticles (CS NPs) have been commonly regarded as potential carriers for the mucosal delivery of therapeutic peptides because of their biocompatibility, bioadhesion and permeation enhancing properties. However, they have limited colloidal stability and readily dissociate and dissolve in the acidic gastric conditions. In the current study, CS NPs were formulated by ionic cross-linking with hydroxypropyl methylcellulose phthalate (HPMCP) as a pH-sensitive polymer and evaluated for the oral delivery of insulin. In vitro results revealed a superior acid stability of CS/HPMCP NPs with a significant control over insulin release and degradation in simulated acidic conditions with or without pepsin. Furthermore, fluorescently-labeled CS/HPMCP NPs showed a 2- to 4-fold improvement in the intestinal mucoadhesion and penetration compared to CS/TPP NPs as evidenced by quantitative fluorescence analysis and confocal microscopy. After s.c. injection to rats, no significant difference in the hypoglycemic effect of insulin solution or insulin-loaded CS/HPMCP NPs was observed, confirming the physico-chemical stability and biological activity of the entrapped peptide. Following peroral administration, CS/HPMCP NPs increased the hypoglycemic effect of insulin by more than 9.8 and 2.8-folds as compared to oral insulin solution and insulin-loaded CS/tripolyphosphate (TPP) NPs, respectively.     

地红霉素肠溶微丸颗粒生物等效性研究

目的 建立测定人血浆中红霉素胺浓度的液相色谱 质谱联用(LC-MS)方法,研究地红霉素肠溶微丸颗粒在健康志愿者中的生物利用度,评价试验制剂和对照制剂的生物等效性.方法采用两制剂双周期自身对照交叉试验设计,20名健康志愿者,单剂量口服地红霉素试验制剂和参比制剂各500 mg,用LC-MS法测定血浆代谢物红霉素胺的浓度.用DAS 软件处理血药浓度数据和计算参数,并进行统计学分析.药物浓度 时间曲线下面积(AUC)及峰浓度(Cmax)经对数转换后作多因数方差分析和双单侧t检验并计算90%可信区间;达峰时间(tmax)进行非参数检验,对两种制剂作出生物等效性评价.结果建立血浆红霉素胺浓度的HPLC-MS测定法.红霉素胺的浓度与吸收峰面积比值在浓度5～1 000 ng.mL^-1范围内呈线性关系,线性回归方程为A＝68.87C+1.47(r＝0.999 7),最低检测浓度为5 ng.mL^-1.低、中、高浓度的方法回收率为98.32%,99.16%,97.87%,平均提取回收率为72.42%,71.63%,73.38%,日内、日间RSD均小于9%.单剂量口服500 mg的地红霉素试验制剂和参比制剂的主要药动学参数AUC0→96分别为(3 537.39±576.32)和(3 065.47±558.63) ng.mL^-1.h,AUC_0→∞分别为(4 059.27±737.25)和(3 831.76±687.51) ng.mL^-1.h;C_max分别为(415.84±81.24)和(420.36±63.21) ng.mL^-1;t_max为(3.25±0.28)和(3.47±0.35)h.受试制剂的相对生物利用度为(105.72±17.83)%.结论LC-MS测定法适用于测定人血浆中红霉素胺的浓度.统计分析结果表明,两种制剂的主要药动学参数之间无明显差异,两种制剂具有生物等效性.     

Pharmacokinetics and safety of montelukast in children aged 3 to 6 months

The single-dose population estimate of the area under the concentration-time curve (AUC(pop)) from time zero to infinity (AUC(0-infinity)), maximum plasma concentration (C(max)), and time to C(max) (t(max)) of montelukast 4-mg oral granules were investigated in infants aged 3 to 6 months. Montelukast concentrations were quantitated after a single 4-mg dose of montelukast oral granules. Pharmacokinetic parameters were determined using a population-based approach with a nonlinear mixed-effect, 1-compartment model with first-order absorption and elimination. Ninety-five percent confidence intervals for the AUC(pop) ratio (3 to 6 months/6 to 24 months) were determined. Safety and tolerability were assessed. Montelukast 4-mg oral granules in children 3 to 6 months of age yielded systemic exposure (AUC(pop) = 3644.3 +/- 481.5 ng x h/mL) similar to that observed in children aged 6 to 24 months (3226.6 +/- 250.0 ng x h/mL). Systemic exposure after a 4-mg dose of montelukast as oral granules is similar in children aged 3 to 6 months and 6 to 24 months.     

Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers

Plasma concentrations of antimicrobial drugs have long been used to correlate exposure with effect, yet one cannot always assume that unbound plasma and tissue concentrations are similar. Knowledge about unbound tissue concentrations is important in the development of antimicrobial drugs, since most infections are localised in tissues. Therefore, a clinical microdialysis study was conducted to evaluate the distribution of tedizolid (TR-700), the active moiety of the antimicrobial prodrug tedizolid phosphate (TR-701), into interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissues following a single oral 600 mg dose of tedizolid phosphate in fasting conditions. Twelve healthy adult subjects were enrolled. Two microdialysis probes were implanted into the thigh of each subject, one into the vastus medialis muscle and one into subcutaneous adipose tissue. Probes were calibrated using retrodialysis. Dialysate samples were collected every 20 min for 12h following a single oral dose of 600 mg tedizolid phosphate, and blood samples were drawn over 24h. Unbound tedizolid levels in plasma were similar to those in muscle and adipose tissue. The ratios of unbound (free) AUC in tissues over unbound AUC in plasma (fAUC(tissue)/fAUC(plasma)) were 1.1 ± 0.2 and 1.2 ± 0.2 for adipose and muscle tissue, respectively. The median half-life was 8.1, 9.2 and 9.6h for plasma, adipose tissue and muscle tissue, respectively. Mean protein binding was 87.2 ± 1.8%. The study drug was very well tolerated. The results of this study show that tedizolid distributes well into ISF of adipose and muscle tissues. Unbound levels of tedizolid in plasma, adipose tissue and muscle tissue were well correlated. Free plasma levels are indicative of unbound levels in the ISF of muscle and adipose tissues.     

Comparative in vitro dissolution and in vivo bioequivalence of 2 pentoxifylline sustained release formulations

Pentoxifylline is a xanthine derivative that is indicated for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. In the present study, prior to the in vivo study, an in vitro comparative dissolution test was performed by the paddle method for 2 oral sustained release pentoxifylline tablets (400 mg) following the bioequivalence guidance of FDA. Metrics of peak exposure (Cmax) and total exposure to 24 h (AUC24) were compared using a randomized, single oral, open-label, 2-period, 2-sequence, 2 treatments crossover study in 24 healthy male volunteers under fasted conditions. After an overnight fast, the volunteers received 400 mg pentoxifylline and the blood samples were collected over a 24-h period following drug administration. Plasma drug concentrations were measured by a reverse-phase HPLC method with ultraviolet detection. In vitro dissolution tests requirements were met by both formulations. Observed exposure metrics for test and reference products were 140.6±51.5 and 132.6±48.5 ng/ml for Cmax and 986.4±350.7 and 1 035.8±350.3 ng.h/ml for AUC0-24 respectively. The confidence intervals (90%) around ratios (test/reference) of least squares means derived from logarithmic transformed exposure metrics were 0.9912-1.1564% for Cmax and 0.8886-1.0535% for AUC0-24. Therefore it can be concluded that both products are bioequivalent in terms of peak and total exposure and therefore interchangeable.     

Safety, tolerability, and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans

This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (+/-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t(max)) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R(O), calculated from AUC(0-tau) (day 8)/AUC(0-tau) (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.     

Absolute bioavailability of moxonidine

In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean +/- standard deviation] 3438 +/- 962 pg.h/ml (AUC(0----Tlast)) and 3674 +/- 1009 pg.h/ml (AUC(0----infinity)) for treatment A; 3855 +/- 1157 pg.h/ml (AUC(0----Tlast)) and 4198 +/- 1205 pg.h/ml (AUC(0----infinity)) for treatment B. Mean peak plasma concentrations of 1495 +/- 646 pg/ml were attained at 0.56 +/- 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 +/- 1342 pg/ml at 0.17 +/- 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h)) in absolute figures and as percentage of the dose administered were 102 +/- 26 micrograms or 51 +/- 13% for the tablet and 122 +/- 33 micrograms or 61 +/- 16% for the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic studies of green tea catechins in maternal plasma and fetuses in rats

We carried out a pharmacokinetic study to determine the levels and profiles of catechins in pregnant rats and their fetuses after ingestion of green tea extract (GTE). We measured total catechin levels after enzyme digestions. Dams, at 15.5 days of gestation, were fed with GTE and catechins were measured in the maternal plasma, placenta, and fetus 0, 0.5, 1, 2, 3, 5, 8, 10, 12, 16, and 20 h after maternal GTE intake. The pharmacokinetic changes were analyzed by non compartmental models. We found that maternal plasma concentrations of catechins were about 10 times higher than in placenta and 50-100 times higher than in the fetus. AUC and Cmax levels of (-)-epicatechin (EC) were the highest in plasma while the levels of (-)-epigallocatechin gallate (EGCG) were the highest in the placenta and the fetus. The exposure level of catechin derivatives was higher than the gallate derivatives in maternal plasma after normalization but reversed in the placenta and fetus. The absorption of epi-isomers in plasma was found to be more favorable than their non epi-isomer counterparts. EGCG had the highest level of exposure (AUC) and the highest Cmax in the fetus, implying it may have potential for in utero antioxidant protection.     

Lung-specific delivery of paclitaxel by chitosan-modified PLGA nanoparticles via transient formation of microaggregates

Chitosan-modified paclitaxel-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles with a mean diameter of 200-300 nm in distilled water were prepared by a solvent evaporation method. The mean diameter increased dramatically in contact with the mouse (CDF(1)) plasma, as a function of chitosan concentration in the modification solution (e.g., 2670.5 nm for 0.7% chitosan-modified nanoparticles, NP(3)), but reverted to almost its original size (i.e., 350.7 nm for NP(3)) following 5 min of gentle agitation. The zeta potential of PLGA nanoparticles was changed to positive by the chitosan modification. The in vitro uptake into, and cytotoxicity of the nanoparticles against, a lung cancer cell line (A549) were significantly increased by the modification. Most importantly, a lung-specific increase in the distribution index of paclitaxel (i.e., AUC(lung)/AUC(plasma)) was observed for chitosan-modified nanoparticles (e.g., 99.9 for NP(3) vs. 5.4 for Taxol) when nanoparticles were administered to lung-metastasized mice via the tail vein at a paclitaxel dose of 10 mg/kg. Transient formation of aggregates in the blood stream followed by enhanced trapping in the lung capillaries, and electrical interaction-mediated enhanced uptake across the endothelial cells of the lung tumor capillary appear to be responsible for the lung-tumor-specific distribution of the chitosan modified nanoparticles.     

Intravenous pharmacokinetics and absolute oral bioavailability of dolasetron in healthy volunteers: part 1

In this first part of a two-part investigation, the intravenous dose proportionality of dolasetron mesylate, a 5-HT3 receptor antagonist, and the absolute bioavailability of oral dolasetron mesylate were investigated. In an open-label, randomized, four-way crossover design, 24 healthy men between the ages of 19 and 45 years received the following doses: 50, 100, or 200 mg dolasetron mesylate administered by 10-min intravenous infusion or 200 mg dolasetron mesylate solution administered orally. Serial blood and urine samples were collected for 48 h after dosing. Following intravenous administration, dolasetron was rapidly eliminated from plasma, with a mean elimination half-life (t1/2) of less than 10 min. Dolasetron was rarely detected in plasma after oral administration of the 200 mg dose. Hydrodolasetron, the active primary metabolite of dolasetron, appeared rapidly in plasma following both oral and intravenous administration of dolasetron mesylate, with a mean time to maximum concentration (t(max)) of less than 1 h. The mean t1/2 of hydrodolasetron ranged from 6.6-8.8 h. The plasma area under the concentration-time curve (AUC0-infinity)) for both dolasetron and hydrodolasetron increased proportionally with dose over the intravenous dose range of 50-200 mg dolasetron mesylate. Approximately 29-33%) and 22% of the dose was excreted in urine as hydrodolasetron following intravenous and oral administration of dolasetron, respectively. For dolasetron as well as hydrodolasetron, mean systemic clearance (C1), volume of distribution (Vd), and t1/2 were similar at each dolasetron dose. The mean 'apparent' bioavailability of dolasetron calculated using plasma concentrations of hydrodolasetron was 76%. The R(+) enantiomer of hydrodolasetron represented the majority of drug in plasma (> 75%) and urine (> 86%). Dolasetron was well tolerated following both oral and intravenous administration.     

Consideration of interaction between nanoparticles and food components for the safety assessment of nanoparticles following oral exposure: A review

Nanoparticles (NPs) are increasingly used in food, and the toxicity of NPs following oral exposure should be carefully assessed to ensure the safety. Indeed, a number of studies have shown that oral exposure to NPs, especially solid NPs, may induce toxicological responses both in vivo and in vitro. However, most of the toxicological studies only used NPs for oral exposure, and the potential interaction between NPs and food components in real life was ignored. In this review, we summarized the relevant studies and suggested that the interaction between NPs and food components may exist by that 1) NPs directly affect nutrients absorption through disruption of microvilli or alteration in expression of nutrient transporter genes; 2) food components directly affect NP absorption through physico-chemical modification; 3) the presence of food components affect oxidative stress induced by NPs. All of these interactions may eventually enhance or reduce the toxicological responses induced by NPs following oral exposure. Studies only using NPs for oral exposure may therefore lead to misinterpretation and underestimation/overestimation of toxicity of NPs, and it is necessary to assess the synergistic effects of NPs in a complex system when considering the safety of NPs used in food.     

Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP

BACKGROUND AND PURPOSE An ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACH Effects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(-/-) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 μg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTS Curcumin was a potent hBCRP inhibitor in vitro (K(i) 0.70 ± 0.41 μM). Curcumin increased the area under the curve (AUC)(0-8) of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg(-1), but not in Bcrp(-/-) mice. Curcumin increased AUC(0-24) of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose-exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (K(m) 1.7 ± 0.3 μM). Its linear index (dose/K(m)) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONS Curcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose-exposure relationship of sulphasalazine.     

Comparative in vivo evaluation of propranolol hydrochloride after oral and transdermal administration in rabbits.

The purpose of this study was the in vivo evaluation of orally and transdermally administered propranolol hydrochloride in rabbits. Transdermal patches of propranolol hydrochloride (PPN) were formulated employing ethyl cellulose and polyvinylpyrrolidone as film formers. The pharmacodynamic (PD) and pharmacokinetic (PK) performance of PPN following transdermal administration was compared with that of oral administration. This study was carried out in a randomized cross-over design in male New Zealand albino rabbits. The PK parameters such as maximum plasma concentration (C(max)), time for peak plasma concentration (t(max)), mean residence time (MRT) and area under the curve (AUC(0-alpha)) were significantly (P<0.01) different following transdermal administration compared to oral administration. The terminal elimination half-life (t(1/2)) of transdermally delivered PPN was found to be similar to that following oral administration. In contrast to oral delivery, a sustained therapeutic activity was observed over a period of 24 h after transdermal administration compared to oral administration. The relative bioavailability of PPN was increased about fivefold to sixfold after transdermal administration as compared to oral delivery. This may be due to the avoidance of first pass effect of PPN. The sustained therapeutic activity was due to the controlled release of drug into systemic circulation following transdermal administration.