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The most relevant lipase-catalyzed strategies for the synthesis of pharmaceutically important cyclic and acyclic α-, β- and γ-amino carboxylic acid enantiomers through hydrolysis of the corresponding amino carboxylic esters and lactams, over the last decade are overviewed. A brief Introduction part deals with the importance and synthesis of enantiomeric amino acids, and formulates the objectives of the actual work. The strategies are presented in the Main Text, in chronological order, classified as kinetic, dynamic kinetic and sequential kinetic resolution. Mechanistic information of the enzymatic transformations is also available at the end of this overview. The pharmacological importance of the enantiomeric amino acids is given next to their synthesis, in the Main Text, and it is also illustrated in the Conclusions and Outlook sections., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This is a safety assessment of 40 saccharide ester ingredients as used in cosmetics. The saccharide esters are reported to function in cosmetics as emollients, skin-conditioning agents, fragrance ingredients, and emulsion stabilizers. The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the relevant data for these ingredients. The Panel concluded that the saccharide esters are safe in cosmetics in the present practices of use and concentrations described in this safety assessment.

Camostat mesylate, an oral serine protease inhibitor, is used to treat chronic pancreatitis and reflux esophagitis. Recently, camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) were reported to inhibit the infection of cells by severe acute respiratory syndrome coronavirus 2 by inhibiting type II transmembrane serine protease. We conducted a phase I study to investigate high-dose camostat mesylate as a treatment for coronavirus disease 2019. Camostat mesylate was orally administered to healthy adults at 600 mg 4 times daily under either of the following conditions: fasted state, after a meal, 30 min before a meal, or 1 h before a meal, and the pharmacokinetics and safety profiles were evaluated. In addition, the time of plasma GBPA concentration exceeding the effective concentration was estimated as the time above half-maximal effective concentration (EC 50 ) by using pharmacokinetic/pharmacodynamic modeling and simulation. Camostat mesylate was safe and tolerated at all dosages. Compared with the fasted state, the exposure of GBPA after a meal and 30 min before a meal was significantly lower; however, no significant difference was observed at 1 h before a meal. The time above EC 50 was 11.5 h when camostat mesylate 600 mg was administered 4 times daily in the fasted state or 1 h before a meal. Based on the results of this phase I study, we are currently conducting a phase III study., (© 2021 ONO Pharmaceutical Co., Ltd. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Hyperbaric oxygen (HBO 2 ) is breathing >1 atmosphere absolute (ATA; 101.3 kPa) O 2 and is used in HBO 2 therapy and undersea medicine. What limits the use of HBO 2 is the risk of developing central nervous system (CNS) oxygen toxicity (CNS-OT). A promising therapy for delaying CNS-OT is ketone metabolic therapy either through diet or exogenous ketone ester (KE) supplement. Previous studies indicate that KE induces ketosis and delays the onset of CNS-OT; however, the effects of exogeneous KE on cognition and performance are understudied. Accordingly, we tested the hypothesis that oral gavage with 7.5 g/kg induces ketosis and increases the latency time to seizure (LSz) without impairing cognition and performance. A single oral dose of 7.5 g/kg KE increases systemic β-hydroxybutyrate (BHB) levels within 0.5 h and remains elevated for 4 h. Male rats were separated into three groups: control (no gavage), water-gavage, or KE-gavage, and were subjected to behavioral testing while breathing 1 ATA (101.3 kPa) of air. Testing included the following: DigiGait (DG), light/dark (LD), open field (OF), and novel object recognition (NOR). There were no adverse effects of KE on gait or motor performance (DG), cognition (NOR), and anxiety (LD, OF). In fact, KE had an anxiolytic effect (OF, LD). The LSz during exposure to 5 ATA (506.6 kPa) O 2 (≤90 min) increased 307% in KE-treated rats compared with control rats. In addition, KE prevented seizures in some animals. We conclude that 7.5 g/kg is an optimal dose of KE in the male Sprague-Dawley rat model of CNS-OT.

Previously, we found that ONO-2160, an ester-type prodrug of levodopa (3-hydroxy-l-tyrosine), was mainly hydrolyzed in human plasma by α 1 -acid glycoprotein (AGP) with a partial contribution of albumin. In this study, we investigated whether ONO-2160 was hydrolyzed in the plasma of preclinical species (dog, rabbit, rat, and mouse) and humans and whether AGP and albumin are involved in its hydrolysis. ONO-2160 was hydrolyzed to some extent in the plasma of all tested species with the order of magnitude mouse > human > rabbit > rat > dog. Except for dogs, ONO-2160 was partially hydrolyzed by animal AGP and albumin. This indicated that, similar to albumin, AGP possesses esterase-like activity in mice, rats, and rabbits, as well as humans. A comparison of the values of intrinsic clearance per milliliter of plasma demonstrated that AGP was the major contributor to the hydrolysis of ONO-2160 in rabbit plasma, whereas albumin was primarily responsible for the hydrolysis of ONO-2160 in mouse plasma. This was confirmed by experiments using AGP-knockout mouse plasma. This study reports the first evidence for the existence of species differences in the hydrolysis of ONO-2160 in plasma related to the different contributions of AGP and albumin.

Native extracts from orange peels were obtained by a conventional method using acetone and, an alternative method using ionic liquid (1-butyl-3-methylimidazolium chloride ([C 4 mim]Cl)). The bioaccessibilities and cellular uptakes of carotenoids, esters and chlorophylls were evaluated, since the influence of esterification on bioaccessibility and bioavailability is not well established. For this, the extracts were emulsified, submitted to in vitro simulated digestion model according to the INFOGEST protocol, followed by uptake by Caco-2 cells. Compounds were separated, identified and quantified by HPLC-PDA-MS/MS. After digestion, 22.0% and 26.2% of the total carotenoids and 45.9% and 68.7% of the chlorophylls were bioaccessible from the acetone and [C 4 mim]Cl extracts, respectively. The bioaccessibilities of xanthophylls and carotenes were significantly higher than those of the mono- and diesters. The uptake by Caco-2 cells varied from 130.2 to 131.9 ng/mg cell protein for total carotenoids and from 243.8 to 234.2 ng/mg cell protein for chlorophylls in the acetone and [C 4 mim]Cl extracts, respectively. In general, xanthophylls and esters were better absorbed than carotenes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We previously reported that MGS0008 is a selective group II metabotropic glutamate receptor (mGlu2/3 receptor) agonist that is effective in animal models of schizophrenia. MGS0008 is a highly hydrophilic glutamate analog and is therefore expected to show low oral bioavailability in humans. To improve the oral bioavailability of MGS0008, ester prodrugs of MGS0008 were synthesized and their usefulness was evaluated. Among the prodrugs, the l-menthol-ester prodrug 4h demonstrated preferable lipophilicity, good chemical stability, and a high conversion rate to MGS0008 in human and monkey liver microsomes. A pharmacokinetic study in monkeys revealed that the oral bioavailability of MGS0008 after oral dosing of compound 4h was approximately 15-fold higher than that after oral dosing of MGS0008. Based on these findings, a diastereomer of compound 4h (compound 4j, or MGS0274), was selected as a candidate for clinical drug development, and its besylate is currently under development for the treatment of schizophrenia (Development code: TS-134)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Fusidic acid (FA) has previously been shown to be rapidly metabolized in rodents to its C-3 epimer, which has significantly lower antimycobacterial activity relative to FA. This was in part hypothesized to account for FA's lack of in vivo efficacy in a mouse model of tuberculosis despite potent in vitro antimycobacterial activity. In the current work, we hypothesized that C-3 alkyl ester prodrugs of FA would deliver higher levels of the drug and prevent the rapid metabolism observed upon administration of FA in its original form. Pharmacokinetic analysis of FA and its 3-ketofusidic acid metabolite as well as novel C-3 alkyl ester prodrugs of FA revealed that FA has low exposure in mice due to rapid metabolism to a species-specific metabolite, 3-epifusidic acid. The C-3 alkyl ester prodrugs showed improved absorption and tissue distribution in pharmacokinetic and organ distribution experiments. These results support the original objective of the FA C-3 ester prodrugs to improve drug concentrations and tissue distribution.

Lipophenols are regarded as an emerging source of functional food ingredients. However, little is known about their in vivo digestion, absorption, and metabolism. Thus, the pharmacokinetic characteristics in rat and the gut microbial degradation of tyrosol acyl esters (TYr-Es) with fatty acids of C12:0, C18:0, and C18:2 were investigated for the first time. Major metabolites including tyrosol sulfate and tyrosol glucuronide, rather than the parent compounds, were detected in rat plasma after oral administration of TYr-Es. The increased plasma half-life ( T 1/2 ) and mean residence time demonstrated that TYr-Es display a longer duration of action in vivo than TYr, potentially leading to higher oral bioavailability. TYr-Es could be hydrolyzed by the gut microbiota to free TYr, which may result in the appearance of the second absorption peak in pharmacokinetic profiles. Therefore, TYr-Es exhibit improved bioavailability compared to that of TYr because of their prolonged duration of action.

Local presentation of cancer drugs by injectable drug-eluting depots reduces systemic side effects and improves efficacy. However, local depots deplete their drug stores and are difficult to introduce into stiff tissues, or organs, such as the brain, that cannot accommodate increased pressure. We present a method for introducing targetable depots through injection of activated ester molecules into target tissues that react with and anchor themselves to the local extracellular matrix (ECM) and subsequently capture systemically administered small molecules through bioorthogonal click chemistry. A computational model of tissue-anchoring depot formation and distribution was verified by histological analysis and confocal imaging of cleared tissues. ECM-anchored click groups do not elicit any noticeable local or systemic toxicity or immune response and specifically capture systemically circulating molecules at intradermal, intratumoral, and intracranial sites for multiple months. Taken together, ECM anchoring of click chemistry motifs is a promising approach to specific targeting of both small and large therapeutics, enabling repeated local presentation for cancer therapy and other diseases.

Fusidic acid (FA), a natural product fusidane triterpene-based antibiotic with unique structural features, is active in vitro against Mycobacterium tuberculosis , the causative agent of tuberculosis (TB). While possessing good pharmacokinetics in man, FA is rapidly metabolized in rodents, thus complicating proof-of-concept studies in this model. Toward the repositioning of FA as an anti-TB agent, we herein describe the synthesis, activity, and metabolism of FA and semisynthesized ester derivatives in rat liver microsomes, rat plasma, and mycobacterial cell culture. FA and derivative molecules with a free C-3 OH underwent species-specific metabolism to the corresponding 3-OH epimer, 3-epifusidic acid (3-epiFA). FA was also metabolized in rat plasma to form FA lactone. These additional routes of metabolism may contribute to the more rapid clearance of FA observed in rodents. C-3 alkyl and aryl esters functioned as classic prodrugs of FA, being hydrolyzed to FA in microsomes, plasma, and Mycobacterium tuberculosis culture. In contrast, C-3 silicate esters and C-21 esters were inert to hydrolysis and so did not act as prodrugs. The antimycobacterial activity of the C-3 silicate esters was comparable to that of FA, and these compounds were stable in microsomes and plasma, identifying them as potential candidates for evaluation in a rodent model of tuberculosis.

The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 20 sorbitan esters; this report included sorbitan esters that were reviewed in 1985 and 2002, as well as 3 previously unreviewed sorbitan esters (sorbitan undecylenate, sorbitan sesquicaprylate, and sorbitan palmate). Most of the sorbitan esters are reported to function in cosmetics as surfactant-emulsifying agents. The Panel reviewed the data from previous sorbitan ester reports, as well as additional data included in this report, to determine the safety of these ingredients. The Panel concluded that the sorbitan esters included in this safety assessment are safe in cosmetics in the present practices of use and concentration.

Aims: To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development., Methods: Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO 4 . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13)., Results: OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO 4 . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [C max ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (C max  + 18%, AUC +27%) and OBE002 exposure (C max  + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (C max  + 29%, AUC +24%) and markedly increased nifedipine exposure (C max by 2-fold and AUC by 2-fold), which may be clinically significant., Conclusions: The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022., (© 2019 The British Pharmacological Society.)

Background: Lutein ester (LE) is an important carotenoid fatty acid ester. It is a form in which lutein is present in nature and is produced by free non-esterification and fatty acid esterification. LE is one of the safe sources of lutein. Increasing lutein intake can prevent and treat age-related macular degeneration. In addition, it can effectively inhibit gastric cancer, breast cancer, and esophageal cancer. However, the poor aqueous solubility of LE has impeded its clinical applications., Objective: The objective of this study was to prepare lutein ester nanoparticles (LE-NPs) by liquid antisolvent precipitation techniques to improve the bioavailability of LE in vivo and improve eye delivery efficiency., Materials and Methods: The physical characterization of LE-NPs was performed, and their in vitro dissolution rate, in vitro antioxidant capacity, in vivo bioavailability, tissue distribution, and ocular pharmacokinetics were studied and evaluated., Results: The LE freeze-dried powder obtained under the optimal conditions possessed a particle size of ~164.1±4.3 nm. The physical characterization analysis indicated the amorphous form of LE-NPs. In addition, the solubility and dissolution rate of LE-NPs in artificial gastric juice were 12.75 and 9.65 times that of the raw LE, respectively. The bioavailability of LE-NPs increased by 1.41 times compared with that of the raw LE. The antioxidant capacity of LE-NPs was also superior to the raw LE. The concentration of lutein in the main organs of rats treated with the LE-NPs was higher than that in rats treated with the raw LE. The bioavailability of LE-NPs in rat eyeballs was found to be 2.34 times that of the original drug., Conclusion: LE-NPs have potential application as a new oral pharmaceutical formulation and could be a promising eye-targeted drug delivery system., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Hypoxia is an important biochemical and physiological condition associated with uncontrolled growth of tumor. Measurement of hypoxia in tumor tissue may be useful in characterization of tumor progression and monitoring drug treatment. [ 18 F]FMISO is the most widely employed radiotracer for imaging of hypoxic tissue with positron emission tomography (PET). However, it showed relatively low uptake in hypoxic tissues, which led to low target-to-background contrast in PET images. To overcome these shortcomings, two novel 2-fluoroproprioic acid esters, nitroimidazole derivatives 2-fluoropropionic acid 2-(2-nitro-imidazol-1-yl)-ethyl ester (FNPFT, [ 19 F]5) and 2-fluoropropionic acid 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester (FMNPFT, [ 19 F]8), were prepared and tested. Radiolabeling of [ 18 F]5 and [ 18 F]8 was accomplished in 45 min (radiochemical purity >95%, the decay-corrected radiochemical yield of [ 18 F]5 was 11 ± 2%, and that of [ 18 F]8 was 13 ± 2%, n = 5). In vitro cell uptake studies using EMT-6 tumor cells showed that both radiotracers [ 18 F]5 and [ 18 F]8 displayed significantly higher uptake in hypoxic cells than those under normoxic condition, while 2-[ 18 F]fluoropropionic acid (2-[ 18 F]FPA) displayed no difference. Biodistribution studies in mice bearing EMT-6 tumor showed that [ 18 F]5, [ 18 F]8, and 2-[ 18 F]FPA displayed similar tumor and major organ uptakes. Tumor uptake values for all three agents were higher than those of [ 18 F]FMISO, respectively ( P < 0.05). This is likely due to a rapid in vivo hydrolysis of [ 18 F]5 and [ 18 F]8 to their metabolite, 2-[ 18 F]FPA. Micro PET imaging studies in the same EMT-6 implanted mice tumor model also demonstrated that both [ 18 F]5 and [ 18 F]8 displayed similar tumor uptake comparable to that of 2-[ 18 F]FPA. In conclusion, two new fluorine-18 labeled nitroimidazole derivatives, [ 18 F]5 and [ 18 F]8, showed good tumor uptakes in mice bearing EMT-6 tumor. However, in vivo biodistribution results suggested that they were more likely reflect the predominance of in vivo produced metabolite, 2-[ 18 F]FPA, which may not be related to tumor hypoxic condition.

Purpose: Formulations of ω (OM)-3 with adequate bioavailability in the low-fat fed state are advantageous in patients with severe hypertriglyceridemia (HTG), as these patients are advised to adhere to a low-fat diet. The OM3-containing prescription drugs approved by the US Food and Drug administration (FDA) provide OM3 in either ethyl ester (EE) or free fatty acid (FFA) forms. The OM3 FFA form and formulations with micelle-forming ability have shown improved bioavailability versus the EE form. OM3 phospholipid (PL)/FFA, a krill oil-derived OM3 mixture containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) present as PL esters and FFA, is being developed for the treatment of severe HTG. Both forms of OM3 in OM3-PL/FFA are believed to be digested and absorbed more efficiently as compared to OM3 in EE. This hypothesis was tested by comparing the relative bioavailabilities of EPA and DHA from a single 4-g dose administration of OM3-PL/FFA to those the FDA-approved HTG drug OM3-EE in the fed (high-fat meal) and fasted states. The effects of food on the bioavailability of both drugs were also tested., Methods: This open-label, randomized, 4-way crossover bioavailability study was conducted in 56 healthy adults who were randomly assigned to receive a single 4-g dose of OM3-PL/FFA or OM3-EE in the fasted and fed (high-fat meal) states. The relative bioavailabilities of EPA and DHA were compared between the 2 formulations using pharmacokinetic analysis., Findings: In the fasted state, the AUC 0-72 and C max of EPA + DHA were 5- and 2.7-fold higher, respectively, with OM3-PL/FFA versus OM3-EE. These values were 3- and 4-fold lower in the fed state with OM3-PL/FFA versus OM3-EE. On administration of OM3-EE, the AUC 0-72 and C max of EPA + DHA were 25- and 11-fold higher, respectively, in the fed versus the fasted state. A much lower increase (1.7-fold) in the AUC 0-72 of EPA + DHA was observed on administration of OM3-PL/FFA in the fed versus the fasted state, with similar C max values., Implications: These results demonstrate that the bioavailabilities of EPA and DHA with OM3-PL/FFA, as FFA and conjugated to PL, are far less affected by the fat content of a meal as compared to the EPA and DHA EEs in OM3-EE. These findings suggest a potential clinical advantage with OM3-PL/FFA, since patients with HTG are advised to follow a fat-restricted diet., (Copyright © 2019 Acasti Pharma Inc. Published by Elsevier Inc. All rights reserved.)

Breaching of the skin barrier is essential for delivering active pharmaceutical ingredients (APIs) for pharmaceutical, dermatological and aesthetic applications. Chemical permeation enhancers (CPEs) are molecules that interact with the constituents of skin's outermost and rate limiting layer stratum corneum (SC), and increase its permeability. Designing and testing of new CPEs is a resource intensive task, thus limiting the rate of discovery of new CPEs. In-silico screening of CPEs in a rigorous skin model could speed up the design of CPEs. In this study, we performed coarse grained (CG) molecule dynamics (MD) simulations of a multilayer skin lipid matrix in the presence of CPEs. The CPEs are chosen from different chemical functionalities including fatty acids, esters, and alcohols. A multi-layer in-silico skin model was developed. The CG parameters of permeation enhancers were also developed. Interactions of CPEs with SC lipids was studied in silico at three different CPE concentrations namely, 1% w/v, 3% w/v and 5% w/v. The partitioning and diffusion coefficients of CPEs in the SC lipids were found to be highly size- and structure-dependent and these dependencies are explained in terms of structural properties such as radial distribution function, area per lipid and order parameter. Finally, experimentally reported effects of CPEs on skin from the literature are compared with the simulation results. The trends obtained using simulations are in good agreement with the experimental measurements. The studies presented here validate the utility of in-silico models for designing, screening and testing of novel and effective CPEs.

Rationale: Preclinical studies in the search for treatments for several neurodegenerative diseases have identified lanthionine ketimine (LK) and its monoethyl ester derivative (LKE) as potential candidates. An ultrahigh-pressure liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) assay was developed to evaluate bioavailability by measuring these compounds in mouse serum, whole blood and brain tissue., Methods: Following administration of LKE to mice for 3 days in chow at 300 ppm, the animals were sacrificed, and LKE was extracted from serum, whole blood and brain tissues through protein precipitation using cold methanol. To enhance chromatographic separation and electrospray ionization, LK was methylated using diazomethane. Separations were carried out using C 18 reversed-phase UHPLC, and quantitative measurements were obtained using on-line triple-quadruple mass spectrometry with positive ion electrospray ionization, collision-induced dissociation and selected reaction monitoring. Tolbutamide was used as internal standard., Results: LKE showed good recovery ranging from 77-90% in serum and 82-88% in brain tissue. An eight-point standard curve ranging from 0.005 to 4.6 μM was linear (R 2 0.998). The average LKE detected in mouse serum was 277.42 nM, while the concentration in whole blood was 38 nM. Neither LK nor LKE was detected in brain tissues., Conclusions: A rapid quantitative method to measure LKE in mouse serum, whole blood and brain tissues using UHPLC/MS/MS was developed and validated following FDA guidelines. This method is suitable for bioavailability and pharmacokinetic studies., (© 2018 John Wiley & Sons, Ltd.)

OBE022, a new orally active prostaglandin F 2α  receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration-effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration-response analysis showed the absence of QTc prolongation at all doses tested. Two-sided 90% confidence intervals of the geometric mean C max  for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method., (© 2018, The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Aims: Preterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F 2α receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F 2α receptor antagonists under development for treating preterm labour., Methods: We performed a prospective, first in human, Phase I, dose escalation, placebo-controlled, randomized trial at a clinical trial site in the UK. Placebo, single ascending doses of 10, 30, 100, 300, 1000 or 1300 mg, and multiple ascending doses over 7 days of 100, 300 or 1000 mg day -1 ; were administered to postmenopausal female volunteers. Food interaction was additionally evaluated., Results: Subjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events. Observations showed that prodrug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses, reaching exposure levels that were anticipated to be clinically relevant within 1 h following administration. There was no clinically significant food interaction, with peak exposures reduced to 80% and area under the curve staying bioequivalent. The mean half-life of OBE002 ranged between 8 and 11 h following administration of a single dose and 22-29 h after multiple doses., Conclusions: Administration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients., (© 2018 The British Pharmacological Society.)

Background: We synthesized astaxanthin succinate diester (ASD), a novel astaxanthin (AST) derivate, with succinic anhydride and free AST. ASD was purified and characterized using silica gel column chromatography and spectrometry, respectively., Results: The ASD final synthesis rate was 82.63%. A stability test revealed a high AST and ASD retention rate at pH 5.0-7.0. ASD showed better stability than did AST under acidic conditions. Both sample ions showed lower retention rates under Fe 2+ and Fe 3+ states. The ASD metabolic curve showed serum and liver area under the curve from 0 h to time t (AUC 0-t ) values of 45.05 ± 4.58 and 120.38 ± 23.66 µg h -1  mL -1 , respectively. The long-term accumulation was significantly higher in the ASD group than in the AST group, which showed higher accumulation in the heart, muscle and spleen than in other tissues in vivo., Conclusion: The thermal stability and bioavailability of ASD were higher than that of the non-esterified free AST and common free AST, respectively. Additionally, AST accumulation in different tissues of the ASD group was multifold higher than that of free AST. These results prove that ASD may serve as a better source of AST for human nutrition than does free AST. © 2017 Society of Chemical Industry., (© 2017 Society of Chemical Industry.)

Compound- 3 is an oral monophosphate prodrug of gemcitabine. Previous data showed that Compound- 3 was more potent than gemcitabine and it was orally active in a tumor xenograft model. In the present study, the metabolism of Compound- 3 was investigated in several well-known in vitro matrices. While relatively stable in human and rat plasma, Compound- 3 demonstrated noticeable metabolism in liver and intestinal microsomes in the presence of NADPH and human hepatocytes. Compound- 3 could also be hydrolyzed by alkaline phosphatase, leading to gemcitabine formation. Metabolite identification using accurate mass- and information-based scan techniques revealed that Compound- 3 was subjected to sequential metabolism, forming alcohol, aldehyde and carboxylic acid metabolites, respectively. Results from reaction phenotyping studies indicated that cytochrome P450 4F2 (CYP4F2) was a key CYP isozyme involved in Compound- 3 metabolism. Interaction assays suggested that CYP4F2 activity could be inhibited by Compound- 3 or an antiparasitic prodrug pafuramidine. Because CYP4F2 is a key CYP isozyme involved in the metabolism of eicosanoids and therapeutic drugs, clinical relevance of drug-drug interactions mediated via CYP4F2 inhibition warrants further investigation.

Naproxen (nap) is belonging to Non-steriodal anti-inflammatory drugs (NSAIDs) group of drugs that characterized by their free carboxylic group. The therapeutic activity of nap is usually accompanied by GI untoward side effects. Recently synthesized naproxen amides of some amino acid esters prodrugs to mask the free carboxylic group were reported. Those prodrugs showed a promising colorectal cancer chemopreventive activity. The current study aims to investigate the fate and hydrolysis of the prodrugs kinetically in different pH conditions, simulated gastric and intestinal fluids with pHs of 1.2, 5.5 and 7.4 in vitro at 37 °C. The effect of enzymes on the hydrolysis of prodrugs was also studied through incubation of these prodrugs at 37 °C in human plasma and rat liver homogenates. The pharmacokinetic parameters of selected prodrugs and the liberated nap were studied after oral and intraperitoneal administration in male wistar rats. The results showed the hydrolysis of naproxen amides of amino acid esters to nap through two steps first by degradation of the ester moiety to form the amide of nap with amino acid and the second was through the degradation of the amide link to liberate nap. The two reactions were followed and studied kinetically where K 1 and K 2 (rate constants of degradation) is reported. The hydrolysis of prodrugs was faster in liver homogenates than in plasma. The relative bioavailability of the liberated nap in vivo was higher in case of prodrug containing ethyl glycinate moiety than that occupied l-valine ethyl ester moiety. Each of nap. prodrugs containing ethyl glycinate and l-valine ethyl ester moieties appears promising in liberating nap, decreasing direct GI side effect and consequently their colorectal cancer chemopreventive activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A novel pH-sensitive polymeric prodrug of camptothecin (CPT) by polymerizing γ-camptothecin-glutamate N-carboxyanhydride (Glu (CPT)-NCA) on boronate ester-linked poly (ethyleneglycol) (PEG) directly via the amine-initiated ring open polymerization (ROP) has been developed. The resulting amphiphilic prodrug (mPEG-BC-PGluCPT) could self-assemble into nanoparticles and encapsulate doxorubicin (Dox) simultaneously in aqueous solution for dual-drug delivery. The formation of polymeric prodrug micelles (mPEG-BC@PGluCPT) was confirmed by the measurements of critical aggregation concentration (CAC), particle size, and morphology observations. The mPEG-BC@PGluCPT micelles were colloidally stable in solutions for two weeks. Polymeric prodrug micelles mPEG-BC@PGluCPT and Dox-loaded micelles mPEG-BC@PGluCPT⋅Dox showed sustained drug release profiles over 48 h. As expected, drug release was accelerated by the decreasement of pH value from 7.4 to 6.0, which demonstrated pH-dependent manner of drug release. Additionally, it was found that cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles on HepG2 cells was higher than that on HL-7702 cells, especially in culture medium at pH 6.0. The enhanced cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles under acidic condition on HepG2 cells resulted in the higher cytotoxicity of mPEG-BC@PGluCPT⋅Dox micelles at acidic pH than that at pH 7.4.

1. The aim of this study was to evaluate the role of intestinal esterases on the absorption process of tenofovir disoproxil fumarate (TDF). 2. The esterase inhibition capacity of fruit juices (FJs) rich in ester linkages and pharmaceutical excipients (having ester bonds) was performed in vitro by incubating TDF with each FJ and excipient in the intestinal washings. The ex vivo everted gut sac model was also used to evaluate the absorption enhancement capacity of these FJs and excipients. Single-dose oral pharmacokinetic studies were performed by concomitant administration of TDF with each of the selected FJs and excipients. 3. The in vitro and ex vivo studies showed that cremophor-EL and all FJs prevented the metabolism of TDF with grapefruit juice (GFJ) having the highest level of inhibition. Further, the permeability flux of the monoester form of tenofovir was increased by 113% and 212% by cranberry juice (CBJ) and GFJ, respectively. The in vivo studies also showed that both CBJ and GFJ enhanced the oral bioavailability of TDF as the AUC was increased by 24% and 97%, respectively. 4. These results indicate that the prevention of the metabolic conversion of TDF to its monoester form is crucial in increasing the oral absorption of TDF.

We have investigated the accumulation of porphyrins in Propionibacterium acnes (P.acnes) by 5-aminolevulinic acid hydrochloride (ALA) and its esters, ALA methyl ester hydrochloride (mALA), ALA octyl ester hydrochloride (oALA), and ALA benzyl ester hydrochloride (bALA). From the fluorescence spectra of porphyrins accumulated in P.acnes, the order of porphyrin accumulation is as follows: ALA≫mALA≈bALA>oALA (≈0). Moreover, the PDT efficacy is reduced in the order of ALA>mALA≈bALA>oALA (≈without additives). These results confirm that ALA is superior to ALA esters in accumulating porphyrins in P.acnes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Injectable hydrogels with pH-responsiveness and self-healing ability have great potential for anti-cancer drug delivery. Herein, we developed a series of polysaccharide-based self-healing hydrogels with pH-sensitivity as drug delivery vehicles for hepatocellular carcinoma therapy. The hydrogels were prepared by using N-carboxyethyl chitosan (CEC) synthesized via Michael reaction in aqueous solution and dibenzaldehyde-terminated poly(ethylene glycol) (PEGDA). Doxorubicin (Dox), as a model of water-soluble small molecule anti-cancer drug was encapsulated into the hydrogel in situ. Self-healing behavior of the hydrogels was investigated at microscopic and macroscopic levels, and the hydrogels showed rapid self-healing performance without any external stimulus owing to the dynamic covalent Schiff-base linkage between amine groups from CEC and benzaldehyde groups from PEGDA. The chemical structures, rheological property, in vitro gel degradation, morphology, gelation time and in vitro Dox release behavior from the hydrogels were characterized. Injectability was verified by in vitro injection and in vivo subcutaneous injection in a rat. pH-responsive behavior was verified by in vitro Dox release from hydrogels in PBS solutions with different pH values. Furthermore, the activity of Dox released from hydrogel matrix was evaluated by employing human hepatocellular liver carcinoma (HepG2). Cytotoxicity test of the hydrogels using L929 cells confirmed their good cytocompatibility. Together, these pH-responsive self-healing injectable hydrogels are excellent candidates as drug delivery vehicles for liver cancer treatment. STATEMENT OF SIGNIFICANCE: pH-responsive drug delivery system could release drug efficiently in targeted acid environment and minimalize the amount of drug release in normal physiological environment. pH-sensitive injectable hydrogels as smart anti-cancer drug delivery carriers show great potential application for cancer therapy. The hydrogels with self-healing property could prolong their lifetime during implantation and provide the advantage of minimally invasive surgery and high drug-loading ratio. This work reported the design of a series of pH-responsive self-healing injectable hydrogels based on N-carboxyethyl chitosan synthesized in aqueous solution and dibenzaldehyde-terminated poly(ethylene glycol) via a green approach, and demonstrated their potential as intelligent delivery vehicle of doxorubicin for hepatocellular carcinoma therapy via the pH-responsive nature of dynamic Schiff base., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The release kinetics of esterified p-coumaric acid (PCA) and ferulic acid (FA) from rice straw under a mild alkaline condition were investigated to collect fundamental data for the design of a recovery process. The results showed that the straw size, NaOH concentration, and temperature were the key parameters governing release kinetics. The analysis demonstrated that FA is released considerably faster than PCA. The close relationship between lignin and the PCA dissolution indicates a reciprocal and/or simultaneous release. Moreover, PCA is broadly distributed in the lignin network but tends to be located more densely in the lignin fraction which is not easily solubilized by alkaline treatment. In contrast, the release of FA is strongly affected by removal of lignin fraction which is easily solubilized. These results suggest that the release kinetics are controlled by the accessibility of NaOH to their ester sites in the lignin/hemicellulose network, and by their localization., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Fatty acid esters of monochloropropane 1,2-diol (3-MCPD) are processing-induced toxicants and have been detected in several food categories. This study investigated the absorption, distribution, metabolism, and excretion of 3-MCPD esters in Sprague-Dawley (SD) rats using 3-MCPD 1-monopalmitate as the probe compound. The kinetics of 3-MCPD 1-monopalmitate in plasma was investigated using SD rats, and the results indicated that 3-MCPD 1-monopalmitate was absorbed directly in vivo and metabolized. Its primary metabolites in the liver, kidney, testis, brain, plasma, and urine were tentatively identified and measured at 6, 12, 24, and 48 h after oral administration. Structures were proposed for eight metabolites. 3-MCPD 1-monopalmitate was converted to free 3-MCPD, which formed the phase II metabolites. All of the metabolites were chlorine-related chemical components; most of them existed in urine, reflecting the excretion pattern of 3-MCPD esters. Understanding the metabolism of 3-MCPD esters in vivo is critical for assessing their toxicities.

There is a lack of knowledge regarding uptake of phthalate esters (PEs) and other chemicals into the human nail plate and thus, clarity concerning the suitability of human nails as a valid alternative matrix for monitoring long-term exposure. In particular, the relative importance of internal uptake of phthalate metabolites (from e.g. blood) compared to external uptake pathways is unknown. This study provides first insights into the partitioning of phthalate-metabolites between blood and nail using pharmacokinetic (PK) modelling and biomonitoring data from a Norwegian cohort. A previously published PK model (Lorber PK model) was used in combination with measured urine data to predict serum concentrations of DEHP and DnBP/DiBP metabolites at steady state. Then, partitioning between blood and nail was assessed assuming equilibrium conditions and treating the nail plate as a tissue, assuming a fixed lipid and water content. Although calculated as a worst-case scenario at equilibrium, the predicted nail concentrations of metabolites were lower than the biomonitoring data by factors of 44 to 1300 depending on the metabolite. It is therefore concluded that internal uptake of phthalate metabolites from blood into nail is a negligible pathway and does not explain the observed nail concentrations. Instead, external uptake pathways are more likely to dominate, possibly through deposition of phthalates onto the skin/nail and subsequent metabolism. Modelling gaseous diffusive uptake of PEs from air to nail revealed that this pathway is unlikely to be important. Experimental quantification of internal and external uptake pathways of phthalates and their metabolites into the human nail plate is needed to verify these modelling results. However, based on this model, human nails are not a good indicator of internal human exposure for the phthalate esters studied., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Injections of synthetic esters of testosterone are among the most common forms of testosterone application. In doping control, the detection of an intact ester of testosterone in blood gives unequivocal proof of the administration of exogenous testosterone. The aim of the current project was to investigate the detection window for injected testosterone esters as a mixed substance preparation and as a single substance preparation in serum and plasma. Furthermore, the suitability of different types of blood collection devices was evaluated. Collection tubes with stabilizing additives, as well as non-stabilized serum separation tubes, were tested. A clinical study with six participants was carried out, comprising a single intramuscular injection of either 1000 mg testosterone undecanoate (Nebido(®)) or a mixture of 30 mg testosterone propionate, 60 mg testosterone phenylpropionate, 60 mg testosterone isocaproate, and 100 mg testosterone decanoate (Sustanon(®)). Blood was collected throughout a testing period of 60 days. The applied analytical method for blood analysis included liquid-liquid extraction and preparation of oxime derivatives, prior to TLX-sample clean-up and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection. All investigated testosterone esters could be detected in post-administration blood samples. The detection time depended on the type of ester administered. Furthermore, results from the study show that measured blood concentrations of especially short-chained testosterone esters are influenced by the type of blood collection device applied. The testosterone ester detection window, however, was comparable., (Copyright © 2015 John Wiley & Sons, Ltd.)

Ganciclovir (GCV) is utilized as an anti-herpetic agent. Reports from our laboratory have suggested that dipeptide ester prodrugs of GCV exhibit high affinity towards the oligopeptide transporter hPEPT1 and therefore seem to be promising candidates for the treatment of oral herpes virus infections. In this study, we have examined the bio-availability of a dipeptide prodrug of GCV after oral administration in jugular cannulated Sprague-Dawley rats. A new bio-analytical method was developed with Q-TRAP liquid chromatography tandem mass spectroscopy (LC-MS/MS) for simultaneous analysis of GCV, Valine-GCV (VGCV) and Tyrosine-Valine-GCV (YVGCV). Acyclovir (ACV) was used as an internal standard in the analysis. Area under plasma-concentration time curves for total concentration of GCV after oral administration of YVGCV was found to be approximately 200 % more than that of GCV following intestinal absorption. A complete conversion of the dipeptide prodrug (YVGCV) to parent compound, GCV, by hepatic first-pass metabolism was evident due to the absence of intermediate metabolite VGCV and administered prodrug YVGCV. The dipeptide prodrugs of GCV exhibit higher systemic availability of regenerated GCV upon oral administration and thus seem to be promising drug candidate in the treatment of systemic herpes infections.

Selective targeting of cancer cells employing multiple combinations as co-drug holds promise for new generation therapeutics. Betulinic acid (BA), a plant secondary metabolite kills cancer cells and Dichloroacetate (DCA) is capable of reversing the Warburg phenotype by inhibiting pyruvate dehydrogenase kinase (PDK). Here, we report synthesis, characterization and tumoricidal potential of a co-drug Bet-CA, where a DCA molecule has been appended on C-3 hydroxyl group of BA to generate an ester derivative for increased solubility and subsequent cleavage by internal esterase(s) to release one unit each of BA and DCA. In vitro studies revealed pronounced synergistic cytotoxicity of Bet-CA against a broad spectrum of cancer cells and it selectively killed them when co-cultured with human fibroblasts. Bet-CA treatment increased reactive oxygen species (ROS) production, significantly altered mitochondrial membrane potential gradient (ΔΨm); followed by the release of cytochrome c (Cyt c) which prompted cells to undergo mitochondria mediated apoptosis. In vivo experimentation expectedly exhibited tumor inhibitory potential of Bet-CA and clinically achievable doses did not produce any apparent toxicity. Taken together, results suggestively raise an important corollary hypothesis stating that Bet-CA selectively and synergistically combats cancer without producing toxic manifestations and emerges to be the prospect for the new generation therapeutics.

HCV infections are the leading causes for hepatocellular carcinoma and liver transplantation in the United States. Recent advances in drug discovery have identified direct acting antivirals which have significantly improved cure rates in patients. Current efforts are directed towards identification of novel direct acting antiviral targeting different mechanism of actions which could become part of all oral therapies. We recently disclosed the identification of a novel tricyclic indole derived inhibitors of HCV NS5B polymerase that bound to the enzyme close to the active site. In this manuscript we describe further optimization of potency and pharmacokinetics (PK) of these inhibitors to identify compounds in low nM potency against gt-1b. These analogs also demonstrate excellent PK in rats and monkeys when administered as a dimethyl ethyl amino ester prodrug., (Copyright © 2013. Published by Elsevier Ltd.)

To determine the exact structure of previously tentatively identified minor essential-oil constituents of a Chamomile species (Antemis segetalis Ten. (Asteraceae)), we have synthesized a small combinatorial library of 54 regioisomeric allylmethoxyphenyl pentanoates and 2-pentenoates (49 completely new compounds). GC-MS in combination with 1D- and 2D-NMR analyses of the library compounds provided unambiguous data that led to a straightforward identification of the mentioned A. segetalis constituents as eugenyl angelate, 2-methylbutanoate and 3-methylbutanoate (0.21, 0.22, and 0.13 mg/100 g of fresh plant material, respectively). To assess the safety and potential beneficial pharmacological uses of these naturally occurring esters and several other library compounds (these were tested to provide relevant data for a SAR (structure-activity relationship) analysis), we have studied the effect of these compounds in several models of toxicity (acute toxicity against Artemia salina, cytotoxicity against two cell lines (fibroblast and melanoma)), as well as their acetylcholinesterase inhibitory and antibacterial activities. Anthemis segetalis constituents showed low to moderate activity in all tests. The obtained results suggest that the intake of these compounds in naturally available amounts, on their own, would probably not represent a risk to human health but the possible adverse interactions with the plant matrix should not be neglected., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Aconitum carmichaelii Debx. (Fuzi in Chinese) has been widely clinically used to treat heart failure and rheumatism. Whereas its serious toxicity, Radix et Rhizoma Glycyrrhizae (Gancao in Chinese) was combined with it as traditional Chinese medicine (TCM) herb-pair for toxicity reduction and pharmacological effect improvement. Though some previous viewpoints about that has been reported, the underlying interaction mechanism of two herbs remain unknown and definitely worthy of investigating., Aim of Study: In present study, we focus on Fuzi-Gancao herb-pair precipitation (FGP), considering it related to the compatibility mechanism of Fuzi-Gancao herb-pair. The intestinal absorption and pharmacokinetic characters of 3 diester diterpenoid alkaloids in the precipitation were investigated., Materials and Methods: Both everted gut sac model and in situ single-pass intestinal perfusion model were used to investigate rat small intestinal permeability and transport mechanism of aconitine, hypaconitine and mesaconitine. Moreover, by means of determination of the plasma concentration, the pharmacokinetic characters of 3 alkaloid compounds in rats have been developed., Results: In everted gut sac permeability experiment, the permeability of hypaconitine appeared best in ileum. Furthermore, their uptakes were increased in the presence of P-glycoprotein (P-gp) inhibitors. In situ single-pass intestinal perfusion uptake experiment, results revealed that the transport mechanism may fit the active transport mechanism. And 3 alkaloids in FPG could be absorbed well in rats, fitting 2-compartment model with 1(st) order absorption and lag time., Conclusions: Our results in present study indicated that 3 diester diterpenoid alkaloids in FGP could be dissolved out in gastrointestinal tract firstly and then absorbed in blood after oral administration, which could result in prolonging their mean residence time and adding their absorbed doses, avoiding dose dumping. The current study has significant enlightenments for further investigation on the interaction mechanisms of other acid-base herb-pairs as well as Fuzi-Gancao herb-pair., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The systemic bioavailability of free fatty acid (FFA) forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with ethyl ester (EE) forms is dependent on the presence of intestinal lipases and is highest during consumption of high-fat meals. Given that patients with cardiovascular disease are advised to reduce dietary fat intake, potentially lowering the bioavailability and therapeutic benefit, the hypothesis that FFA forms provide for higher bioavailability compared with EE forms under low-fat diet conditions was tested where the pharmacokinetics of the FFA form (Epanova™) were compared with those of an ethyl ester form (Lovaza®) following repeat dosing. Fifty-two healthy male and female subjects were equally allocated to one of two open-label, parallel-group cohorts. Following a Therapeutic Lifestyle Changes diet for a minimum of 7 days, blood samples were drawn for endogenous values for EPA and DHA over a 24-hour period. Subjects were then administered 4 × 1 g capsules of either Epanova (OM3 FFA) or Lovaza (OM3 EE) once daily for 14 days, following which serial blood samples were drawn over a 24-hour period to characterize the bioavailability of EPA and DHA from the respective formulations. In addition, changes from baseline in lipid profile were explored. Systemic bioavailability, as measured by area under the curve from time zero to 24 hours (AUC(0-τ)) and the maximum measured plasma concentrations during the 0-24 hour dosing interval (C(max,ss)) of unadjusted total plasma EPA + DHA were approximately 3-fold and 3.9-fold higher, respectively, for Epanova relative to Lovaza. Following baseline adjustment, the magnitude of difference in bioavailability was approximately 5.8-fold and 6.5-fold higher in AUC(0-τ) and C(max,ss), respectively, for Epanova relative to Lovaza. Serum triglycerides were reduced by a significantly greater extent (P = 0.013) for Epanova relative to Lovaza (21% versus 8%). The bioavailability of the FFA forms of EPA and DHA in Epanova are significantly greater than the bioavailability from the EE forms present in Lovaza under low-fat dietary conditions normally recommended for patients with cardiovascular disease. This increased bioavailability may lead to improved triglyceride-lowering in patients with hypertriglyceridemia.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated to determine the concentration of armillarisin succinate ester in mouse plasma and tissues, used for preclinical evaluation. Bavachin was employed as the internal standard. Separation was performed on a 3.5 µm Zorbax SB-C(18) column (30 × 2.1 mm), with a mobile phase consisting of methanol and aqueous 20 mm ammonium acetate. Both analyte and internal standard were determined using electrospray ionization and the MS data acquisition was via selected ion monitoring in negative scanning mode. Quantification was performed using the transitions m/z 333 → 233 and 323 → 221 for armillarisin succinate ester and internal standard, respectively. The method was validated with respect to linearity, accuracy, precision, recovery and stability. This assay has been successfully applied to a pharmacokinetic and tissue distribution study after intravenous injection of ASE in mouse in a dose of 10 mg/kg., (Copyright © 2012 John Wiley & Sons, Ltd.)

Carboxylesterases (CESs) located in the intestine play an unique role in the absorption of many drugs especially ester prodrugs. In order to determine the expression and hydrolyzing activity of CESs isozymes (CES1 and CES2) located in rat intestine, the activities of CES1 and CES2 were evaluated by the intestinal S9 incubation with imidapril and irinotecan (CPT-11), the substrates of CES1 and CES2, respectively. The distribution characteristics of CES1, CES2, Pregnane X Receptor (PXR) and Constitutive Androstane Receptor were analyzed by real-time polymerase chain reaction (RT-PCR) or Western blot. Imidaprilat metabolized from imidapril by CES1 was too low to be detected in rat intestinal S9 fractions, while there was little and even no expression of CES1 mRNA in intestinal segments. In contrast, Vmax values for CPT-11 diminished gradually from proximal to distal segments within the rat intestine which was consistent with the mRNA expression level of CES2. These results indicated that CES2 represents the major CESs isoform in the rat complete intestine and decreased from duodenum to colon, whereas the expression of CES1 was too low to influence the metabolism of ester prodrugs. The expression of PXR and CAR decreased slightly along the entire intestine on both mRNA and protein levels which indicated that PXR and CAR may be one of the major factors which contribute to the expression of CES1 and CES2. Thus, the knowledge about the characteristic and site-specific expression of CES1 and CES2 in rat intestine will help to predict the oral bioavailability of ester prodrugs.

Phytosterols (plant sterols and stanols) can lower intestinal cholesterol absorption, but the complex dynamics of the lipid digestion process in the presence of phytosterol esters (PEs) are not fully understood. We performed a clinical experiment in intubated healthy subjects to study the time course of changes in the distribution of all lipid moieties present in duodenal phases during 4 h of digestion of meals with 3.2 g PE (PE meal) or without (control meal) PE. In vitro experiments under simulated gastrointestinal conditions were also performed. The addition of PE did not alter triglyceride (TG) hydrolysis in the duodenum or subsequent chylomicron TG occurrence in the circulation. In contrast, cholesterol accumulation in the duodenum aqueous phase was markedly reduced in the presence of PE (-32%, P < 0.10). In vitro experiments confirmed that PE reduces cholesterol transfer into the aqueous phase. The addition of PE resulted in a markedly reduced presence of meal-derived hepta-deuterated cholesterol in the circulation, i.e., in chylomicrons (-43%, PE meal vs. control; P < 0.0001) and plasma (-54%, PE meal vs. control; P < 0.0001). The present data show that addition of PE to a meal does not alter TG hydrolysis but displaces cholesterol from the intestinal aqueous phase and lowers chylomicron cholesterol occurrence in humans.

Fatty acid esters of 3-chloropropane-1,2-diol (3-MCPD) and glycidol are a newly identified class of food process contaminants. They are widespread in refined vegetable oils and fats and have been detected in vegetable fat-containing products, including infant formulas. There are no toxicological data available yet on the 3-MCPD and glycidol esters, and the primary toxicological concern is based on the potential release of 3-MCPD or glycidol from the parent esters by lipase-catalyzed hydrolysis in the gastrointestinal tract. Although 3-MCPD is assessed as a nongenotoxic carcinogen with a tolerable daily intake (TDI) of 2 μg/kg body weight (bw), glycidol is a known genotoxic carcinogen, which induces tumors in numerous organs of rodents. The initial exposure estimates, conducted by Federal Institute for Risk Assessment (BfR) under the assumption that 100% of the 3-MPCD and glycidol are released from their esters, revealed especially that infants being fed commercial infant formula could ingest harmful amounts of 3-MCPD and glycidol. However, the real oral bioavailability may be lower. As this gives rise for toxicological concern, the currently available toxicological data of 3-MCPD and glycidol and their esters are summarized in this review and discussed with regard to data gaps and further research needs., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Perfluorinated carboxylic acids (PFCAs) are ubiquitous in human sera worldwide. Biotransformation of the polyfluoroalkyl phosphate esters (PAPs) is a possible source of PFCA exposure, because PAPs are used in food-contact paper packaging and have been observed in human sera., Objectives: We determined pharmacokinetic parameters for the PAP monoesters (monoPAPs) and PAP diesters (diPAPs), as well as biotransformation yields to the PFCAs, using a rat model., Methods: The animals were dosed intravenously or by oral gavage with a mixture of 4:2, 6:2, 8:2, and 10:2 monoPAP or diPAP chain lengths. Concentrations of the PAPs and PFCAs, as well as metabolic intermediates and phase II metabolites, were monitored over time in blood, urine, and feces., Results: The diPAPs were bioavailable, with bioavailability decreasing as the chain length increased from 4 to 10 perfluorinated carbons. The monoPAPs were not absorbed from the gut; however, we found evidence to suggest phosphate-ester cleavage within the gut contents. We observed biotransformation to the PFCAs for both monoPAP and diPAP congeners., Conclusions: Using experimentally derived biotransformation yields, perfluorooctanoic acid (PFOA) sera concentrations were predicted from the biotransformation of 8:2 diPAP at concentrations observed in human serum. Because of the long human serum half-life of PFOA, biotransformation of diPAP even with low-level exposure could over time result in significant exposure to PFOA. Although humans are exposed directly to PFCAs in food and dust, the pharmacokinetic parameters determined here suggest that PAP exposure should be considered a significant indirect source of human PFCA contamination.

Background: There is a debate currently about whether different chemical forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are absorbed in an identical way. The objective of this study was to investigate the response of the omega-3 index, the percentage of EPA+DHA in red blood cell membranes, to supplementation with two different omega-3 fatty acid (n-3 FA) formulations in humans., Design: The study was conducted as a double-blinded placebo-controlled trial. A total of 150 volunteers was randomly assigned to one of the three groups: (1) fish oil concentrate with EPA+DHA (1.01 g+0.67 g) given as reesterified triacylglycerides (rTAG group); (2) corn oil (placebo group) or (3) fish oil concentrate with EPA+DHA (1.01 g+0.67 g) given as ethyl ester (EE group). Volunteers consumed four gelatine-coated soft capsules daily over a period of six months. The omega-3 index was determined at baseline (t(0)) after three months (t(3)) and at the end of the intervention period (t(6))., Results: The omega-3 index increased significantly in both groups treated with n-3 FAs from baseline to t(3) and t(6) (P<0.001). The omega-3 index increased to a greater extent in the rTAG group than in the EE group (t(3): 186 versus 161% (P<0.001); t(6): 197 versus 171% (P<0.01))., Conclusion: A six-month supplementation of identical doses of EPA+DHA led to a faster and higher increase in the omega-3 index when consumed as triacylglycerides than when consumed as ethyl esters.

Objectives: The aim of the study was to compare iodine utilization from different sources by sows and their progeny and the levels of T3 and T4 in their serum., Design: Pregnant Czech Large White × Landrace sows were fed with an experimental KPK diet (a diet for lactating sows) 14 days before parturition until weaning (at a piglet age of 28 days). In group A (n=50, 10 sows, 40 piglets) the feed was supplemented with KI (0.6 mg of iodine per kg of feed). Iodine enriched alga Chlorella spp. (0.6 mg of iodine per kg of feed) was used as a supplement in group B (n=50, 10 sows, 40 piglets). In group C (n=50, 10 sows, 40 piglets) the sows were injected i.m. with IFAE at a dose of 100 mg of iodine per sow. Iodine, T3 and T4 were measured in each group for comparison of iodine utilization., Results: The use of IFAE resulted in higher serum concentrations in sows compared to KI and alga. In contrast, iodine concentrations in milk and piglets were lower when IFAE were used. We found a wide variation in the concentrations of T3 and T4 in the serum of piglets in all groups., Conclusion: Our results indicate a good utilization of iodized oil by sows. However, its transfer into milk is lower compared to the other iodine sources.

EXP3174 is the major active metabolite of losartan, a drug currently widely used for the treatment of cardiovascular diseases. This study was designed to evaluate the physicochemical properties of EXP3174-pivoxil (a novel synthesized prodrug of EXP3174) and characterize its metabolism, regional intestinal absorption and pharmacokinetics by in vitro and in vivo studies. An in vitro metabolism study was conducted in liver and intestinal S9 fractions from different species including rat, dog and human. In vivo absorption was investigated following regional intestinal dosing in rats, and the pharmacokinetics was determined using rats after a single oral administration. EXP3174-pivoxil exhibited predictable stability in the aqueous solution within a pH range of 1.2-9.0 as well as in the solid form of powder. An in vitro metabolism study revealed that EXP3174-pivoxil was rapidly and efficiently converted into EXP3174 by enzymatic hydrolysis. The dose administered into the duodenum and jejunum resulted in higher values for the AUC(0-24h) and C(max) than those following ileum dosing (p < 0.05). Furthermore, the AUC(0-24h) and C(max) values for EXP3174 increased in a dose-dependent manner as dose increased from 0.5 to 5 mg/kg. A comparable AUC(0-24h), shortened T(max) and a significant increase in the plasma C(max) of EXP3174 were observed following oral administration of EXP3174-pivoxil (as EXP3174, 1 mg/kg) compared with those of losartan (as EXP3174, 5 mg/kg) in rats, suggesting faster absorption and a 5-fold enhancement in the bioavailability of EXP3174. These results suggest that EXP3174-pivoxil may serve as a more effective drug even at lower clinical doses by exhibiting increased bioavailability and faster therapeutic response, compared with losartan.

Preclinical studies have shown that docosahexaenoic acid (DHA) derived from microalgae (DHASCO) is neither mutagenic nor toxic in acute, subchronic or developmental tests. DHASCO, triglyceride oil from the fermentation of Crypthecodinium cohnii, contains 40-50% (400-500 mg/g) of DHA by weight. Martek Biosciences Corporation has developed a concentrated ethyl ester of DHA (900 mg/g) from DHASCO (MATK-90). A 90-day subchronic safety study with a one-month recovery period using Sprague-Dawley rats included clinical observations, ophthalmic examination, hematology, clinical chemistry, toxicokinetic evaluation, and pathological assessments. Effects of MATK-90 were compared with those produced from DHASCO and control (corn oil). Doses of MATK-90 (1.3, 2.5 and 5.0 g/kg/day) and DHASCO (5.0 g/kg/day=2g of DHA) were administered once-daily by oral gavage at a volume of 10 mL/kg. The corn oil was also administered by oral gavage (10 mL/kg/day). There were no treatment-related adverse effects in any of the parameters measured at doses of

The aim of this study was to investigate the effects of different ester groups in position 5' of stavudine on the transdermal penetration with and without the use of Pheroid™ as the delivery system. Six esters were prepared by reaction of stavudine with six different acid chlorides at room temperature. Female human abdominal skin was used for in vitro penetration in Franz diffusion cells. The experimental aqueous solubility of stavudine (104.75 mg/mL) was much higher than that of the synthesized derivatives (ranging from 0.08 to 5.17 mg/mL), while the log D (octanol-buffer partition coefficient) of stavudine (-0.85) was lower than that of its derivatives (ranging from -0.41 to 3.06). The experimental transdermal flux of stavudine (6.52 µmol/cm(2).h) in PBS (phosphate buffer solution) was much higher than that of any of its derivatives (0.06 - 0.23 µmol/cm(2).h), while the propionyl (6.64 µmol/cm(2).h) and the butyryl esters (6.87 µmol/cm(2).h) had the highest transdermal flux using the Pheroid™ (0.75 - 6.87 µmol/cm(2).h) system.

Cellulose acetate (CA) fibers loaded with the ester prodrugs of naproxen, including methyl ester, ethyl ester and isopropyl ester, were prepared through electrospinning using acetone/N,N-dimethylacetamide(DMAc)/ethanol (4:1:1, v/v/v) as solvent. The chemical and morphological characterizations of the medicated fibers were investigated by means of SEM, DSC, XRD and FTIR, as well as the studies of the drug release properties. The results indicated that the morphology and diameter of the fibers were influenced by the concentration of spinning solution, applied voltage, electrospun solvent and the surfactants. The average diameters of the fibers ranged between 100 and 500 nm for three prodrugs. There was good compatibility between CA and three prodrugs in the blended fibers, respectively. In vitro release indicated that constant drug release from the fiber was observed over 6 days. The prodrugs were successfully encapsulated into the fibers, and this system was stable in terms of effectiveness in release.

Both mRNA and protein levels of the carboxylesterase (CES) isozymes, hCE1 and hCE2, in Caco-2 cells increase in a time-dependent manner, but hCE1 levels are always higher than those of hCE2. In human small intestine, however, the picture is reversed, with hCE2 being the predominant isozyme. Drugs hydrolyzed by hCE1 but not by hCE2 can be hydrolyzed in Caco-2 cells, but they are barely hydrolyzed in human small intestine. The results in Caco-2 cells can be misleading as a predictor of what will happen in human small intestine. In the present study, we proposed a novel method for predicting the absorption of prodrugs in the absence of CES-mediated hydrolysis in Caco-2 cells. The specific inhibition against CES was achieved using bis-p-nitrophenyl phosphate (BNPP). The optimal concentration of BNPP was determined at 200 microM by measuring the transport and hydrolysis of O-butyryl-propranolol (butyryl-PL) as a probe. BNPP concentrations of more than 200 microM inhibited 86% of hydrolysis of butyryl-PL, resulting in an increase in its apparent permeability. Treatment with 200 microM BNPP did not affect paracellular transport, passive diffusion, or carrier-mediated transport. Furthermore, the proposed evaluation system was tested for ethyl fexofenadine (ethyl-FXD), which is a superior substrate for hCE1 but a poor one for hCE2. CES-mediated hydrolysis of ethyl-FXD was 94% inhibited by 200 microM BNPP, and ethyl-FXD was passively transported as an intact prodrug. From the above observations, the novel evaluation system is effective for the prediction of human intestinal absorption of ester-type prodrugs.