Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]₃) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-[Irinotecan]₃ undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]_3‒x (x = 1,2) and PEG-[linker] during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-[Irinotecan]₃ displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]₃ were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-[Irinotecan]₃ displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-[Irinotecan]₃ is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.

During the analysis of benziamidazole-class irreversible proton pump inhibitors,an unusual mass spectral response with the mass-to-charge ratio at[M+10]+intrigued us,as it couldn't be assigned to any literature known relevant structure,intermediate or adduct ion.Moreover,this mysterious mass pattern of[M+10]+has been gradually observed by series of marketed proton pump inhibitors,viz.omeprazole,pantoprazole,lansoprazole and rabeprazole.All the previous attempts to isolate the corresponding component were unsuccessful.The investigation of present work addresses this kind of signal to a pyridinium thiocyanate mass spectral intermediate(10),which is the common fragment ion of series of labile aggregates.The origin of such aggregates can be traced to the reactive intermediates formed by acid-promoted degradation.These reactive intermediates tend to react with each other and give raise series of complicated aggregates systematically in a water/acetonitrile solution by electrospray ioniza-tion.The structure of the corresponding pyridinium thiocyanate species of omeprazole(10a)has been eventually characterized with the help of synthetic specimen(10a').Our structural proposal as well as its origin was supported by in situ nuclear magnetic resonance,chemical derivatization and colorimetric experiments.

d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS, also known as vitamin E-TPGS) is a biodegradable amphiphilic polymer prepared by esterification of vitamin E with polyethylene glycol (PEG) 1000. It is approved by the US Food and Drug Administration (FDA) and has found wide application in nanocarrier drug delivery systems (NDDS). Fully characterizing the in vivo fate and pharmacokinetic behavior of TPGS is important to promote the further development of TPGS-based NDDS. However, to date, a bioassay for the simultaneous quantitation of TPGS and its metabolite, PEG1000, has not been reported. In the present study, we developed such an innovative bioassay and used it to investigate the pharmacokinetics, tissue distribution and excretion of TPGS and PEG1000 in rat after oral and intravenous dosing. In addition, we evaluated the interaction of TPGS with cytochromes P450 (CYP450s) in human liver microsomes. The results show that TPGS is poorly absorbed after oral administration with very low bioavailability and that, after intravenous administration, TPGS and PEG1000 are mainly distributed to the spleen, liver, lung and kidney before both being slowly eliminated in urine and feces as PEG1000. In vitro studies show the inhibition of human CYP450 enzymes by TPGS is limited to a weak inhibition of CYP3A4. Overall, our results provide a clear picture of the in vivo fate of TPGS which will be useful in evaluating the safety of TPGS-based NDDS in clinical use and in promoting their further development.

Monomethoxy poly(ethylene glycol)-

With the rapid development of nanotechnology, the research and development of nanomedicine has become one of the current development directions of drug innovation. The pharmacokinetic characteristics of nanomedicine are significantly different from general drugs because of the scale effect based on nanostructures, and pharmacokinetics studies of nanomedicine may be different from the general drugs. This article focuses on the research strategies and considerations on non-clinical pharmacokinetics of nanomedicine, including test agents, in vivo/in vitro assays, biological sample analysis, data evaluation and analysis etc., providing references for developers.

The development of nano drug delivery systems (NDDSs) provides new approaches to fighting against diseases. The NDDSs are specially designed to serve as carriers for the delivery of active pharmaceutical ingredients (APIs) to their target sites, which would certainly extend the benefit of their unique physi-cochemical characteristics, such as prolonged circulation time, improved targeting and avoiding of drug-resistance. Despite the remarkable progress achieved over the last three decades, the understanding of the relationships between the in vivo pharmacokinetics of NDDSs and their safety profiles is insufficient. Analysis of NDDSs is far more complicated than the monitoring of small molecular drugs in terms of structure, composition and aggregation state, whereby almost all of the conventional techniques are inadequate for accurate profiling their pharmacokinetic behavior in vivo. Herein, the advanced bio-analysis for tracing the in vivo fate of NDDSs is summarized, including liquid chromatography tandem-mass spectrometry (LC-MS/MS), F(o)rster resonance energy transfer (FRET), aggregation-caused quench-ing (ACQ) fluorophore, aggregation-induced emission (AIE) fluorophores, enzyme-linked immunosor-bent assay (ELISA), magnetic resonance imaging (MRI), radiolabeling, fluorescence spectroscopy, laser ablation inductively coupled plasma MS (LA-ICP-MS), and size-exclusion chromatography (SEC). Based on these technologies, a comprehensive survey of monitoring the dynamic changes of NDDSs in struc-ture, composition and existing form in system (i.e. carrier polymers, released and encapsulated drug) with recent progress is provided. We hope that this review will be helpful in appropriate application methodology for investigating the pharmacokinetics and evaluating the efficacy and safety profiles of NDDSs.

Because many therapeutic agents are contaminated by epimeric impurities or form epimers as a result of metabolism, analytical tools capable of determining epimers are increasingly in demand. This article is a proof-of-principle report of a novel DMS-MS/MS method to separate and simultaneously quantify epimers, taking PGF2 and its 8-epimer, 8--PGF2, as an example. Good accuracy and precision were achieved in the range of 10-500 ng/mL with a run time of only 1.5 min. Isopropanol as organic modifier facilitated a good combination of sensitivity and separation. The method is the first example of the quantitation of epimers without chromatographic separation.

Nanoliposomes are considered to be the most successful nanoparticle drug delivery system, but their fate in vivo has not been fully understood due to lack of reliable bioanalytical methods, which seriously limits the development of liposomal drugs. Hence, an overview of currently used bioanalytical methods is imperative to lay the groundwork for the need of developing a bioanalytical method for liposome measurements in vivo. Currently, major analytical methods for nanoliposomes measurement in vivo include fluorescence labeling, radiolabeling, magnetic resonance imaging (MRI), mass spectrometry and computed tomography.In this review, these bioanalytical methods are summarized, and the advantages and disadvantages of each are discussed. We provide insights into the applicability and limitations of these analytical methods in the application of nanoliposomes measurement in vivo, and highlight the recent development of instrumental analysis techniques. The review is devoted to providing a comprehensive overview of the investigation of nanoliposomes design and associated fate in vivo, promoting the development of bioanalytical techniques for nanoliposomes measurement, and understanding the pharmacokinetic behavior, effectiveness and potential toxicity of nanoliposomes in vivo.

A simple and high throughput method was developed and validated for simultaneous determination of valproic acid and its two toxicant ene-metabolites, 2-enevalproic acid and 4-enevalproic acid in epilepsy patient plasma using liquid chromatography–tandem mass spectrometry. Probenecid was used as in-ternal standard and solid-phase extraction was selected for sample preparation. A chromatographic separation was performed on an Agilent Poroshell SB-C18 column (50 mm ? 4.6 mm i.d., 2.7μm) by an optimized gradient elution at a flow rate of 0.9 mL/min. The total run time was 7 min. Electrospray ionization was used in negative ion mode by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 143.0-143.0 for valproic acid, m/z 140.9-140.9 for 2-enevalproic acid and 4-enevalproic acid for their poor fragments, and m/z 283.9-239.9 for probenecid. The results showed good linearity of valproic acid, 2-enevalproic acid and 4-enevalproic acid in their respective linear ranges. The correlation coefficients were more than 0.998. The intra- and inter-day precision of the assay was less than 11.0%and the accuracy ranged from 2%to 12%. This analytical method was successfully applied to assay plasma concentrations of valproic acid and its two ene-metabolites in epilepsy patient plasma and used for therapeutic drug monitoring.

The present study establishes a visualization method for the measurement of the distribution and localization of protein/peptide constituents within a single poly-lactide-co-glycolide (PLGA) microsphere using synchrotron radiation-based Fourier-transform infrared spectromicroscopy (SR-FTIR). The representative infrared wavenumbers specific for protein/peptide (Exenatide) and excipient (PLGA) were identified and chemical maps at the single microsphere level were generated by measuring and plotting the intensity of these specific bands. For quantitative analysis of the distribution within microspheres, Matlab software was used to transform the map file into a 3D matrix and the matrix values specific for the drug and excipient were extracted. Comparison of the normalized SR-FTIR maps of PLGA and Exenatide indicated that PLGA was uniformly distributed, while Exenatide was relatively non-uniformly distributed in the microspheres. In conclusion, SR-FTIR is a rapid, nondestructive and sensitive detection technology to provide the distribution of chemical constituents and functional groups in microparticles and microspheres.