Tumor-targeting peptide functionalized PEG-PLA micelles for efficient drug delivery.

Because of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, block copolymer micelles are widely utilized for chemotherapy drug delivery. In order to further improve the anti-tumor ability and reduce unwanted side effects of drugs, tumor-targeting peptides were used to functionalize the surface of polymer micelles so that the micelles can target tumor tissues. Herein, we synthesized a kind of PEG-PLA that is maleimide-terminated and then conjugated with a specific peptide F3 which revealed specific capacity binding to nucleolin that is overexpressed on the surface of many tumor cells. Then, F3 conjugated, paclitaxel loaded nanoparticles (F3-NP-PTX) were prepared as stable micelles that displayed an enhanced accumulation via a peptide-mediated cellular association in human breast cancer cells (MCF-7). Furthermore, F3-NP-PTX showed a prominent anti-tumor efficacy compared with non-targeting nanoparticles (NP-PTX) both in vitro and in vivo, and showed great potential as an efficacious targeting drug delivery system for breast cancer treatment.

Effect of Xiao-Ai-Ping injection on paclitaxel pharmacokinetics in rats by LC-MS/MS method.

Xiao-Ai-Ping injection (XAP) has been shown to be clinically effective in treatment of gastric carcinoma, liver cancer and lung cancer, when it was combined with anticancer drug paclitaxel (PTX). To analyze the effect of XAP on the pharmacokinetics of PTX, a liquid chromatography-tandem mass spectroscopy (LCMS/MS) assay method was developed and validated to quantify PTX simultaneously and its main metabolite 3'-p-hydroxypaclitaxel (C3'-OHP) in rat plasma. PTX and C3'-OHP were quantified using positive MRM mode. The analysis method was validated for specificity, recovery, carry-over, accuracy, precision, sample stability and dilution integrity under various storage conditions. The pharmacokinetic parameters were determined in rats after tail intravenous administration of 6 mg/mL PTX in the absence (control group) or presence of intraperitoneal administration of 10 mL/kg、20 mL/kg XAP (study groups). Compared to control group, the area under the plasma concentration-time curve (AUC) of PTX and C3'-OHP in study groups increased significantly following consecutive administration with XAP for 10 days. In conclusion, pretreatment with XAP enhanced the exposure of PTX and C3'-OHP. There would be herb-drug interaction happening between XAP and PTX in rats.

Improving systemic circulation of paclitaxel nanocrystals by surface hybridization of DSPE-PEG2000.

This paper aims to improve the systemic circulation of paclitaxel (PTX) by modifying nanocrystals with DSPE-PEG 2000. PTX nanocrystals (PNCs) were prepared by an anti-solvent method and DSPE-PEG 2000 was inserted into PNCs by hybridization. The average size of DSPE-PEG-PNCs did not change obviously compared to the naked PNCs, but the negative charge increased after hybridization. The saturated attachment ratio of DSPE-PEG 2000 was 0.4%. In vitro release rate of DSPE-PEG-PNCs was significantly slower than that of PTX solution and the naked PNCs, which indicated that DSPE-PEG 2000 hindered the release of PTX. Moreover, pharmacokinetics results showed that DSPE-PEG-PNCs achieved a higher area-under-the-curve (AUC, 4.43 ±â€¯0.19 mg/L*h) and lower clearance rate (1.08 ±â€¯0.16 L/h/kg) compared to PNCs with an AUC of 2.48 ±â€¯0.18 mg/L*h and a clearance rate of 1.89 ±â€¯0.15 L/h/kg. Therefore, DSPE-PEG-PNCs could have a significant potential in clinical use by improving the systemic circulation of the drug.

Bioequivalence of paclitaxel protein-bound particles in patients with breast cancer: determining total and unbound paclitaxel in plasma by rapid equilibrium dialysis and liquid chromatography-tandem mass spectrometry.

Background and objective: Paclitaxel protein-bound particles for injectable suspension (nab-paclitaxel) showed many advantages in safety, effectiveness, and convenience. Different from conventional formulations, the bioequivalence evaluation of nab-paclitaxel formulations requires to determine the total amount of paclitaxel in plasma and the unbound paclitaxel to reflect their in vivo disposition. This study aimed to develop an analytical method to quantify the total and unbound paclitaxel in plasma and evaluate the bioequivalence of two formulations of nab-paclitaxel in patients with breast cancer. Materials and methods: An open-label, randomized, two-period crossover study was completed among 24 Chinese patients with breast cancer. The patients were randomized to receive either the test formulation on cycle 1 day 1 and after 21 days in cycle 2 day 1 by the reference formulation (Abraxane®), or vice versa. Rapid equilibrium dialysis was adopted to separate the unbound paclitaxel in human plasma. Total and unbound paclitaxel concentrations were measured by the validated liquid chromatography-tandem mass spectrometry methods over the range of 5.00-15,000 and 0.200-200 ng/mL, respectively. The bioequivalence of the test formulation to the reference formulation was assessed using the Food and Drug Administration and European Medicines Agency guidelines. Results: All the 90% confidence intervals (CIs) of the geometric mean ratios fell within the predetermined acceptance range. The 90% CIs for the area under the concentration-time curve (AUC) from 0 h to 72 h (AUC0-t), AUC from time zero to infinity (AUC0-∞), and peak plasma concentrations (Cmax) for total paclitaxel were 92.03%-98.05%, 91.98%-99.37%, and 91.37%-99.36%, respectively. The 90% CIs of AUC0-t, AUC0-∞, and Cmax for unbound paclitaxel were 86.77%-97.88%, 86.81%-97.88%, and 87.70%-98.86%, respectively. Conclusion: Bioequivalence between the two nab-paclitaxel formulations was confirmed for total and unbound paclitaxel at the studied dose regimen.

Quantitation of paclitaxel, and its 6-alpha-OH and 3-para-OH metabolites in human plasma by LC-MS/MS.

We have developed a high performance liquid chromatography mass spectrometry method for quantitating paclitaxel and its 6-alpha-OH and 3-para-OH metabolites in 0.1 mL human plasma. After MTBE liquid-liquid extraction, chromatographic separation was achieved with a Phenomenex synergy polar reverse phase (4 µm, 2 mm × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an ABI SCIEX 4000Q with electrospray, positive-mode ionization. The assay was linear from 10-10,000 ng/mL for paclitaxel and 1-1000 ng/mL for both metabolites and proved to be accurate (94.3-110.4%) and precise (<11.3%CV). Recovery from plasma was 59.3-91.3% and matrix effect was negligible (-3.5 to 6.2%). Plasma freeze thaw stability (90.2-107.0%), stability for 37 months at -80 °C (89.4-112.6%), and stability for 4 h at room temperature (87.7-100.0%) were all acceptable. This assay will be an essential tool to further define the metabolism and pharmacology of paclitaxel and metabolites in the clinical setting. The assay may be utilized for therapeutic drug monitoring of paclitaxel and may also reveal the CYP2C8 and CYP3A4 activity phenotype of patients.

Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors.

Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic data collected in the phase 1 clinical trial were utilized for the development of a population POP PK by implementing the non-linear mixed effects approach. Patient characteristics at study entry were evaluated as covariates in the model. Subjects (N = 26) were treated at nine dosage levels (1.2-12.4 mg/m2/day) on a daily × 5 schedule. Hematological toxicity data were modeled against exposure metrics. Results A two-compartment POP PK model best described the disposition of AR-67 by fitting a total of 328 PK observations from 25 subjects. Following covariate model selection, age remained as a significant covariate on central volume. The final model provided a good fit for the concentration versus time data and PK parameters were estimated with good precision. Clearance, inter-compartmental clearance, central volume and peripheral volume were estimated to be 32.2 L/h, 28.6 L/h, 6.83 L and 25.0 L, respectively. Finally, exposure-pharmacodynamic analysis using Emax models showed that plasma drug concentration versus time profiles are better predictors of AR-67-related hematologic toxicity were better predictors of leukopenia and thrombocytopenia, as compared to total dose. Conclusions A POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmax and AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted.

A polymeric micelle with an endosomal pH-sensitivity for intracellular delivery and enhanced antitumor efficacy of hydroxycamptothecin.

Amphiphilic poly(ethylene glycol)-imino-poly(benzyl-l-aspartate) (PIPA) and poly(ethylene glycol)-poly(benzyl-l-aspartate) (PPA) block copolymers were synthesized as pH-responsive and pH-nonresponsive copolymers, respectively. Polymer micelles were fabricated by the film dispersion method, and hydroxycamptothecin (HCPT) was physically encapsulated into the micelles. The average diameter of the HCPT-loaded PIPA micelles (PIPAH micelles) was approximately 230 nm, which was slightly smaller than that of the HCPT-loaded PPA micelles (PPAH micelles, approximately 260 nm). The drug-loading content and encapsulation efficiency of the PIPAH micelles (3.33% and 68.89%, respectively) were slightly higher than those of the PPAH micelles (2.90% and 59.68%, respectively). The PIPAH micelles exhibited better colloid stability, storage stability, and plasma stability than the PPAH micelles. Drug release from the PIPAH micelles with imino groups was pH dependent, and more than 75% or 65% of the loaded HCPT was released within 24 h in weakly acidic media (pH 5.0 or 6.0, respectively). An in vitro cell assay demonstrated that the pH-sensitive micelles exhibited potent suppression of cancer cell proliferation and little cytotoxicity on normal cells. Additionally, these micelles could be efficiently internalized by the tumor cells through macropinocytosis- and caveolin-mediated endocytotic pathways. HCPT-loaded micelles had longer circulation time than the HCPT solution in a pharmacokinetic study. In vivo antitumor experiments indicate that the PIPAH micelles had better antitumor efficacy than the pH-insensitive PPAH micelles and the HCPT solution. Therefore, the pH-responsive PIPAH micelles have great potential for high-efficiency delivery of HCPT. STATEMENT OF SIGNIFICANCE: In this study, a new type of pH-responsive amphiphilic copolymer, poly(ethylene glycol)-imino-poly(benzyl-l-aspartate) (PIPA) block copolymer, was synthesized. This copolymer had then self-assembled to form nanomicelles for tumor intracellular delivery of hydroxycamptothecin (HCPT) for the first time. In in vitro test, the PIPAH micelles exhibited adequate stability and pH-dependent drug release. To one's excitement, the PIPAH micelles exhibited better antitumor efficacy and biosafety than the pH-insensitive micelles (PPAH) and the HCPT solution in in vitro and in vivo antitumor experiments. Therefore, the pH-responsive micelles in this study have significant potential to be used for high-performance delivery of HCPT and potentially for the targeted delivery of other cancer therapeutic agents. The polymer designed in this study can be used as a carrier of poorly soluble drugs or other active ingredients.

Population pharmacokinetic model of irinotecan and its metabolites in patients with metastatic colorectal cancer.

PURPOSE: Irinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment. METHODS: We used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates. RESULTS: The final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499. CONCLUSION: CPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.

Chemotherapy in pregnancy: exploratory study of the effects of paclitaxel on the expression of placental drug transporters.

Introduction The use of paclitaxel in pregnant cancer patients is feasible in terms of fetal safety, but little is known about the effects of paclitaxel on the placenta. Using three experimental models, we aimed to assess the effects of paclitaxel on the expression of placental drug transporters. Methods In the in vitro model (human primary trophoblast culture), trophoblasts were isolated from normal term placentas and subsequently exposed to paclitaxel. The transcriptional regulation of 84 genes encoding for drug transporters, and the protein expression of ABCB1/P-gp and ABCG2/BCRP were assessed. In the in vivo model, placental tissues isolated from pregnant cancer patients treated with paclitaxel were analyzed to assess the protein expression of ABCB1/P-gp and ABCG2/BCRP. The same parameters were assessed in extracts from human placental cotyledons perfused ex vivo with paclitaxel. Results In the in vitro model, the expression of twelve drug-transporters genes was found to be significantly down-regulated after exposure to paclitaxel, including ABCC10, SLC28A3, SLC29A2, and ATP7B (involved in the transport of taxanes, antimetabolites, and cisplatin, respectively). The protein expression of ABCB1/P-gp increased by 1.3-fold after paclitaxel administration. Finally, the protein expression of ABCB1/P-gp and ABCG2/BCRP was higher in cotyledons from mothers treated with multiple doses of paclitaxel during pregnancy than in cotyledons perfused with a single dose of paclitaxel. Discussion Paclitaxel modulates the expression of placental drug transporters involved in the disposition of various anticancer agents. Further studies will be needed to assess the impact of repeated or prolonged exposure to paclitaxel on the expression and function of placental drug transporters.

A new method for the determination of total and released docetaxel from docetaxel-entrapped core-crosslinked polymeric micelles (CriPec®) by LC-MS/MS and its clinical application in plasma and tissues in patients with various tumours.

A sensitive, high-performance liquid chromatographic method was developed and validated, for determination of docetaxel from docetaxel-entrapped core-crosslinked polymeric micelles (CriPec®) in human potassium EDTA plasma and released docetaxel to support the clinical development of Cripec® docetaxel. CriPec® docetaxel is a novel formulation of docetaxel - covalently conjugated via a linker agent in a nanoparticle. The analytical characterization of CriPec® docetaxel comprises determination of both released and total docetaxel, the first being the already deconjugated docetaxel, whereas total is representative of all docetaxel (deconjugated as well as CriPec® nanoparticle conjugated material). Total docetaxel was determined by incubation of human plasma with 0.5 M ammonium acetate buffer pH 7.4 for 3-days at 37 °C. Hereafter, a liquid-liquid extraction with 1-chlorobutane was performed using paclitaxel as internal standard. Released docetaxel from CriPec® docetaxel nanoparticles was determined in human plasma stabilized with 5 M ammonium acetate, pH 5.0. Hereafter, a liquid-liquid extraction with 1-chlorobutane was performed using docetaxel-d5 in acetonitrile as internal standard. Released docetaxel and its internal standard were eluted. The validated ranges for total docetaxel were 2,000-100,000 ng/mL for the high concentrations and 2-500 ng/mL for the low concentrations and 0.250-100 ng/mL for released docetaxel. In conclusion the newly developed assay met the required standards for validation and was applied successfully to support pharmacokinetic analysis in both serum and tissue in patients treated with Cripec®.

Ursolic acid loaded intra nasal nano lipid vesicles for brain tumour: Formulation, optimization, in-vivo brain/plasma distribution study and histopathological assessment.

The aim was to formulate an optimized ursolic acid (UA) loaded lipid vesicle using formulation by design approach (FbD) for improving the drug targeting by nasal route for brain tumor. Three factors were evaluated at three different levels using anethole (terpene) (A), ethanol (B) and phospholipid90 G (C) as independent variables and their individual and combined effects were observed for PDI (Y1), vesicle size (Y2) and encapsulation efficiency (Y3) to select an optimal system (UALVopt). The optimized formulation was further converted into gel and evaluated for drug release, nasal permeation study, brain/plasma uptake and histopathology study. The UALVopt formulation containing anethole as terpene (1% as A), ethanol (2.6% as B) and phospholipid90 G (8.8 mg as C) showed low PDI (0.212), vesicle size (115.56 nm) and high entrapment efficiency (76.42%). The in-vitro drug release and ex-vivo permeation study results revealed prolonged drug release and permeation. The brain/blood ratio for UALVGopt remained significantly higher at all the time points with respect to UALVopt indicating higher and prolonged retention of drug at site of action. The histopathological study of the nasal mucosa and brain confirmed non-toxic nature of developed formulation. The formulation UALVGopt could serve as a better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its efficacy.

Practical fluorimetric assay for the detection of anticancer drug SN-38 in human plasma.

The implementation of therapeutic drug monitoring in the routine clinical practice in oncology is mainly limited by the lack of therapeutic indexes for the majority of the anticancer drugs, and by the absence of suitable analytical tools, which can accurately quantify in real time the concentration of the administered drugs and their relevant metabolites in biological fluids. In this work, a simple and efficient fluorimetric determination of SN-38, the active metabolite of the anticancer drug irinotecan, was developed and applied to human plasma samples. The intrinsic fluorescence of SN-38 allowed its quantification in the range 10-500 ng mL-1 with a LOQ of 5.0 ng mL-1 and a LOD of 1.5 ng mL-1. Low interferences due to main metabolites of irinotecan and comedications, commonly associated with administration of irinotecan, were observed. A validation study, according to FDA and EMA guidelines for bioanalytical method validation, was carried out and, finally, blind samples were analyzed in parallel with a HPLC-MS method obtaining an excellent agreement between the two techniques.

Simultaneous quantification of Gemcitabine and Irinotecan hydrochloride in rat plasma by using high performance liquid chromatography-diode array detector.

In this manuscript we aimed at the simultaneous separation and quantification of Gemcitabine and Irinotecan hydrochloride (injected both as single components and in combination) from Sprague Dawley rat plasma by using a validated method obtained through the use of a High Performance Liquid Chromatography (HPLC)-diode array detector (DAD). Gemcitabine and Irinotecan hydrochloride were detected and quantified using a Zorbax Extend C-18 column (250 mm × 4.6 mm; 5 µm particle size) in gradient elution mode. The chromatographic analyses were carried out in 15 min. The analytical mode was calibrated and validated in the concentration range from 0.1 to 18 µg/mL both for Gemcitabine and Irinotecan hydrochloride. Sprague Dawley rat plasma was used to perform the analysis. 3-methylxanthine was the internal standard. The weighted-matrix matched standard curves of Gemcitabine and Irinotecan hydrochloride showed a good linearity up to 18 µg/mL. Parallelism tests were also performed to evaluate whether the over-range samples could be analyzed after dilution without affecting the analytical performance. The intra- and inter-day precision (RSD%) values of Gemcitabine and Irinotecan hydrochloride were ≤7.14% and ≤11.5%, respectively. The intra- and inter-day trueness (Bias%) values were in the range from -11.5% to 1.70% for both drugs. The analytical mode performance was further tested after collecting Sprague Dawley rat plasma following a single-dose administration of chemotherapeutics or their association. The validated HPLC-DAD method allowed the simultaneous quantification of Gemcitabine and Irinotecan hydrochloride in the rat plasma, besides the evaluation of the pharmacokinetic parameters and drug delivery.

Polysorbate 20 alters the oral bioavailability of etoposide in wild type and mdr1a deficient Sprague-Dawley rats.

The aim of the present work was to investigate the ability of nonionic surfactants to increase the oral absorption of the P-glycoprotein substrate etoposide in vitro and in vivo. Intestinal absorption was investigated by studying bidirectional permeability of etoposide across filter-grown Caco-2 and MDCKII MDR1 cell monolayers. The oral absorption of etoposide was investigated in wild type (WT) and mdr1a deficient (KO) Sprague-Dawley rats. In cell cultures, polysorbate 20 (PS20) decreased P-glycoprotein mediated efflux of etoposide. When PS20 and etoposide were co-administered to WT rats, the oral absorption of etoposide increased significantly in the presence of 5 and 25% (v/v) PS20. However, in KO rats, the exposure of etoposide after oral co-administration with 5% PS20 was similar to control. Unexpectedly, co-administration of etoposide with 25% PS20 significantly reduced the absorption fraction of etoposide in mdr1a KO rats. In vitro dialysis studies performed on PS20-containing etoposide solutions suggested that the reduced bioavailability may be due to etoposide retention in PS20 micelles and/or through increased viscosity. In conclusion, PS20 increases oral bioavailability of etoposide through inhibition of P-glycoprotein. However, the use of the excipient may be challenged by etoposide retention at higher concentrations.

TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

BACKGROUND: Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. OBJECTIVE: To evaluate the association of pharmacokinetic parameter TC > 0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. METHODS: A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxel™ kit. The patients' PTX TC > 0.05 (the time during which PTX plasma concentration exceed 0.05µmol/L) were calculated based on pharmacokinetic analysis. RESULTS: The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 µmol/L; (2) the PTX TC > 0.05 ranged from 14 to 38h with a median time of 27h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC > 0.05 between CR+PR and SD+PD; (4) with the increasing value of TC > 0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC > 0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC > 0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC > 0.05 at 26 to 30h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. CONCLUSION: PTX TC > 0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors.

pH-Mediated molecular differentiation for fluorimetric quantification of chemotherapeutic drugs in human plasma.

At present, drug dosage is based on standardised approaches that disregard pharmakokinetic differences between patients and lead to non-optimal efficacy and unnecessary side effects. In this work, we demonstrate the potential of pH-mediated fluorescence spectroscopy for therapeutic drug monitoring in complex media. We apply this principle to the simultaneous quantification of the chemotherapeutic prodrug Irinotecan and its active metabolite SN-38 from human plasma across the clinically relevant concentration range, i.e. from micromolar to nanomolar at molar ratios of up to 30 : 1.

Prediction of neutrophil reduction using plasma paclitaxel concentration after administration in patients with uterine, ovarian, or cervical cancers in an outpatient clinic.

PURPOSE: Plasma paclitaxel (PTX) concentration 24 h or later after PTX administration may predict myelosuppression. Here, we explored predictive markers for neutropenia induced by intravenous administration of PTX in an outpatient clinic. METHODS: Thirty women suffering from uterine, ovarian or cervical cancer were enrolled in this study. PTX (mean dose: 167 mg/m2) was intravenously infused and followed by carboplatin. Plasma samples were obtained 4 h after PTX administration. Genotyping was carried out for CYP3A5*3, ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T. RESULTS: There was no significant relationship between genotype and reduced neutrophil count. Neutrophil reduction rate correlated with the patient's height, neutrophil count on the day of administration, and plasma PTX concentration. Multiple regression analysis with those three indices explained 47.7% of the interindividual variability of the neutrophil reduction rate. The model with plasma PTX concentration, patient's height, and plasma 6-α-hydroxy-paclitaxel /PTX concentration ratio also explained 30.0% of the interindividual variability for the neutrophil nadir count after PTX administration. CONCLUSIONS: These results indicate that neutrophil reduction after PTX administration can be partially predicted by multiple regression analysis involving plasma concentration data collected at outpatient clinics.

Analysis of different innovative formulations of curcumin for improved relative oral bioavailability in human subjects.

PURPOSE: The optimal health benefits of curcumin are limited by its low solubility in water and corresponding poor intestinal absorption. Cyclodextrins (CD) can form inclusion complexes on a molecular basis with lipophilic compounds, thereby improving aqueous solubility, dispersibility, and absorption. In this study, we investigated the bioavailability of a new γ-cyclodextrin curcumin formulation (CW8). This formulation was compared to a standardized unformulated curcumin extract (StdC) and two commercially available formulations with purported increased bioavailability: a curcumin phytosome formulation (CSL) and a formulation of curcumin with essential oils of turmeric extracted from the rhizome (CEO). METHODS: Twelve healthy human volunteers participated in a double-blinded, cross-over study. The plasma concentrations of the individual curcuminoids that are present in turmeric (namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were determined at baseline and at various intervals after oral administration over a 12-h period. RESULTS: CW8 showed the highest plasma concentrations of curcumin, demethoxycurcumin, and total curcuminoids, whereas CSL administration resulted in the highest levels of bisdemethoxycurcumin. CW8 (39-fold) showed significantly increased relative bioavailability of total curcuminoids (AUC0-12) in comparison with the unformulated StdC. CONCLUSION: The data presented suggest that γ-cyclodextrin curcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.

Self-assembled phospholipid-based phytosomal nanocarriers as promising platforms for improving oral bioavailability of the anticancer celastrol.

Celastrol (CST) is a promising natural drug of herbal origin that gained a great interest in the recent years by virtue of its wide variety of pharmacological actions. Nowadays, CST is extensively studied as a natural anticancer surrogate with a potential activity against various types of cancers. However, CST suffers from many limitations that handicapped its clinical utility such as limited aqueous solubility and poor gastrointestinal absorption which resulted into its low oral bioavailability. This work spotlights, for the first time, development of self-assembled phytosomal nanocarriers (CST-PHY) for improving CST solubility and oral bioavailability. First CST-phospholipid complex was prepared by a simple solvent evaporation technique. Formation of CST-phospholipid complex was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR), powder X-ray diffraction (XRD) and partition coefficient determination. After dispersion into deionized water, CST-phospholipid complex was self-assembled to form CST-PHY. The optimized CST-PHY demonstrated a nanometric particle size of 178.4±7.07nm and a negative zeta potential of -38.7±3.61mV. Comparative in-vitro release study showed the ability of phytosomes to significantly enhance CST release compared with crude drug and physical mixture. Pharmacokinetic studies in rabbits revealed significant improvement in CST-PHY oral bioavailability compared with crude CST evidenced by 4-fold increase in AUC0-8 and 5-fold increase in Cmax of CST-PHY compared with crude CST. Conclusively, the results confirmed the potential of phytosomal nanocarriers to improve CST oral delivery paving the way for its use for oral cancer therapy.

Determination of irinotecan, SN-38 and SN-38 glucuronide using HPLC/MS/MS: Application in a clinical pharmacokinetic and personalized medicine in colorectal cancer patients.

BACKGROUND: Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G. METHODS: A 100 µL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G. RESULTS: In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G. CONCLUSION: This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study.