Palmitic acid-rich oils with and without interesterification lower postprandial lipemia and increase atherogenic lipoproteins compared with a MUFA-rich oil: A randomized controlled trial.

BACKGROUND: Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism. OBJECTIVES: To test the impact of a commonly consumed IE compared with a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil [rapeseed oil (RO)]. METHODS: A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n = 20) aged 45-75 y. Postprandial plasma triacylglycerol and lipoprotein responses (including stable isotope tracing) to a test meal (50 g fat) were evaluated over 8 h. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM). RESULTS: Plasma triacylglycerol 8-h incremental area under the curves were lower following non-IE compared with RO [-1.7 mmol/L⋅h (95% CI: -3.3, -0.0)], but there were no differences between IE and RO or IE and non-IE. LDL particles were smaller following IE and non-IE compared with RO (P = 0.005). Extra extra large, extra large, and large VLDL particle concentrations were higher following IE and non-IE compared with RO at 6-8 h (P < 0.05). No differences in the appearance of [13C]palmitic acid in plasma triacylglycerol were observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of SFAs compared with RO. CONCLUSIONS: Interesterification did not modify fat digestion, postprandial lipemia, or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA-rich fats, increased proatherogenic large triacylglycerol-rich lipoprotein remnant and small LDL particles following the SFA-rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFAs to cardiovascular disease risk.

Separation of postprandial lipoproteins: improved purification of chylomicrons using an ApoB100 immunoaffinity method.

Elevated levels of triglyceride-rich lipoproteins (TRLs), both fasting and postprandial, are associated with increased risk for atherosclerosis. However, guidelines for treatment are defined solely by fasting lipid levels, even though postprandial lipids may be more informative. In the postprandial state, circulating lipids consist of dietary fat transported from the intestine in chylomicrons (CMs; containing ApoB48) and fat transported from the liver in VLDL (containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because of the difficulty in separating these particles by ultracentrifugation. CM fractions have considerable contamination from VLDL (purity, 10%). To separate CMs from VLDL, we produced polyclonal antibodies against ApoB100 and generated immunoaffinity columns. TRLs isolated by ultracentrifugation of plasma were applied to these columns, and highly purified CMs were collected (purity, 90-94%). Overall eight healthy unmedicated adult volunteers (BMI, 27.2 ± 1.4 kg/m2; fasting triacylglycerol, 102.6 ± 19.5 mg/dl) participated in a feeding study, which contained an oral stable-isotope tracer (1-13C acetate). We then used this technique on plasma samples freshly collected during an 8 h human feeding study from a subset of four subjects. We analyzed fractionated lipoproteins by Western blot, isolated and derivatized triacylglycerols, and calculated fractional de novo lipogenesis. The results demonstrated effective separation of postprandial lipoproteins and substantially improved purity compared with ultracentrifugation protocols, using the immunoaffinity method. This method can be used to better delineate the role of dietary sugar and fat on postprandial lipids in cardiovascular risk and explore the potential role of CM remnants in atherosclerosis.

Lipid nanoparticles for amphotericin delivery in the treatment of American tegumentary leishmaniasis.

Leishmaniasis occurs in the five continents and represents a serious public health challenge, but is still a neglected disease, and the current pharmacological weaponry is far from satisfactory. Triglyceride-rich nanoparticles mimicking chylomicrons (TGNP) behave metabolically like native chylomicrons when injected into the bloodstream. Previously we have shown that TGNP as vehicle to amphothericin B (AB) for treatment of fungi infection showed reduced renal toxicity and lower animal death rates compared to conventional AB. The aim of the current study was to test the tolerability and effectiveness of the TGNP-AB preparation in a murine model of Leishmania amazonensis infection. The in vitro assays determined the cytotoxicity of TGNP-AB, AB, and TGNP in macrophages and promastigote forms and the leishmanicidal activity in infected macrophages. The in vivo toxicity tests were performed in healthy mice with increasing doses of TGPN-AB and AB. Then, animals were treated with 2.5 mg/kg/day of AB, 17.5 mg/kg/day of TGNP-AB, or TGNP three times a week for 4 weeks. TGNP-AB formulation was less cytotoxic for macrophages than AB. TGNP-AB was more effective than AB against the promastigotes forms of the parasite and more effective in reducing the number of infected macrophages and the number of amastigotes forms per cell. TGNP-AB-treated animals showed lower hepatotoxicity. In addition, TGNP-AB group showed a marked reduction in lesion size on the paws and parasitic load. The TGNP-AB preparation attained excellent leishmanicidal activity with remarkable lower drug toxicity at very high doses that, due to the toxicity-buffering properties of the nanocarrier, become fully tolerable.

Glucagon-like peptide-2 mobilizes lipids from the intestine by a systemic nitric oxide-independent mechanism.

AIM: To test the hypothesis that gut hormone glucagon-like peptide-2 (GLP-2) mobilizes intestinal triglyceride (TG) stores and stimulates chylomicron secretion by a nitric oxide (NO)-dependent mechanism in humans. METHODS: In a randomized, single-blind, cross-over study, 10 healthy male volunteers ingested a high-fat formula followed, 7 hours later, by one of three treatments: NO synthase inhibitor L-NG -monomethyl arginine acetate (L-NMMA) + GLP-2 analogue teduglutide, normal saline + teduglutide, or L-NMMA + placebo. TG in plasma and lipoprotein fractions were measured, along with measurement of blood flow in superior mesenteric and coeliac arteries using Doppler ultrasound in six participants. RESULTS: Teduglutide rapidly increased mesenteric blood flow and TG concentrations in plasma, in TG-rich lipoproteins, and most robustly in chylomicrons. L-NMMA significantly attenuated teduglutide-induced enhancement of mesenteric blood flow but not TG mobilization and chylomicron secretion. CONCLUSIONS: GLP-2 mobilization of TG stores and stimulation of chylomicron secretion from the small intestine appears to be independent of systemic NO in humans.

Chylomicron mimicking nanocolloidal carriers of rosuvastatin calcium for lymphatic drug targeting and management of hyperlipidemia.

The present work entails development of novel phospholipid-based self-nanoemulsifying systems (SNES) of rosuvastatin calcium for improving the oral biopharmaceutical performance via intestinal lymphatic pathways. The phospholipid complex-loaded SNES exhibited emulsification time of 142 s, particle size of 182.5 nm, polydispersity index of 0.35, zeta potential of -22.5 mV and complete in vitro drug release within 3 h. Cell line study on Caco-2 indicated absence of cytotoxicity and excellent cellular uptake of PL-SNES vis-à-vis plain SNES. Permeability study revealed >85% enhancement in the permeation, while intestinal perfusion study showed 2.9 and 3.5-fold increase in the permeation and absorption of the drug from the optimized PL-SNES over the pure drug suspension. Nearly 2.2 and 7.2-folds improvement in AUC0-t and Cmax, and 0.33-fold reduction in the Tmax of drug was observed for PL-SNES vis-à-vis the pure drug suspension during pharmacokinetic study. Moreover, PL-SNES also showed superior antihyperlipidemic activity over the pure drug suspension during pharmacodynamic study. Overall, the developed nanoformulation yielded significant improvement in the oral deliverability of the explored drug candidate.

[18F]BODIPY-triglyceride-containing chylomicron-like particles as an imaging agent for brown adipose tissue in vivo.

Brown adipose tissue (BAT) is present in human adults and the current gold standard to visualize and quantify BAT is [18F]FDG PET-CT. However, this method fails to detect BAT under insulin-resistant conditions associated with ageing and weight gain, such as type 2 diabetes. The aim of this study was to develop a novel triglyceride-based tracer for BAT. For this purpose we designed a dual-modal fluorescent/PET fatty acid tracer based on commercially available BODIPY-FL-C16, which can be esterified to its correspondent triglyceride, radiolabeled and incorporated into pre-synthesized chylomicron-like particles. BODIPY-FL-C16 was coupled to 1,2-diolein with a subsequent radiolabeling step resulting in [18F]BODIPY-C16-triglyceride that was incorporated into chylomicron-like particles. Various quality control steps using fluorescent and radioactive methods were conducted before BAT visualization was tested in mice. Triglyceride synthesis, radiolabeling and subsequent incorporation into chylomicron-like particles was carried out in decent yields. This radiotracer appeared able to visualize BAT in vivo, and the uptake of the radiotracer was stimulated by cold exposure. The here reported method can be used to incorporate radiolabeled triglycerides into pre-synthesized chylomicron-like particles. Our approach is feasible to visualize and quantify the uptake of triglyceride-derived fatty acids by BAT.

Chylomicron mimicking solid lipid nanoemulsions encapsulated enteric minicapsules targeted to colon for immunization against hepatitis B.

The oral route is one of the most convenient routes for drug and/or vaccine delivery. Yet variable nature of gastrointestinal tract due to transient changes in pH, physiology, and flora throughout the gut together with hostile nature of peptide drugs/vaccines when given by this route results in limited success. Colon targeting is a recent area of interest for most of the research among which hard gelatin coated capsules is one such important and useful contrivance. The present study assesses the mucosal immunization with HBsAg loaded lyophilized nanoparticles delivered in the colonic region using enteric coated minicapsules. Designed minicapsules offers better compliance and oral vaccine antigen delivery to the colonic region which involving mucosal exposure thus mimicking the natural pathogen entry in the body. The present study is an extension of our reported work where nanoparticles were administered to the colon through the rectal route. Lyophilized nanoparticles were characterized for particle size, in-vitro release and antigen integrity along with cell uptake study. Particles had ~241 ±â€¯32 nm sizes, flattened yet spherical in morphology. Enteric coated minicapsules were evaluated for size, coating thickness, and dissolution profile. In-vivo immune response assured its immunogenic potential with profound IgG (485 ±â€¯41 mIU/ml) and IgA (885 ±â€¯126 mIU/ml) antibody production as compared to marketed recombinant hepatitis B antigen formulation (Gene Vac-B®) which induce IgG and IgA titer; 1027 ±â€¯62 mIU/ml and 220 ±â€¯11 mIU/ml respectively following well established immunization protocol. Former induced significant mucosal immunity due to the involvement of Common Mucosal Immune System (CMIS). The study supports the workable novel approach for immune protection against hepatitis B.

Chylomicron-pretended nano-bio self-assembling vehicle to promote lymphatic transport and GALTs target of oral drugs.

Lymphatic transport of oral drugs allows extraordinary gains in bioavailability and efficacy through avoidance of first-pass hepatic metabolism and preservation of drugs at lymphatic tissues against lymph-mediated diseases. Chylomicrons can transport dietary lipids absorbed from the intestine to the tissues through lymphatic circulation. Herein, we engineered for the first time a chylomicron-pretended mesoporous silica nanocarrier that utilizes the digestion, re-esterification, and lymphatic transport process of dietary triglyceride to promote lymphatic transport of oral drugs. Taking lopinavir (LNV) as a model antiretroviral drug with disadvantages such as poor solubility, high first-pass effect and off-target deposition, this vehicle exhibited several properties belonging to ideal nanocarriers, including high drug load, amorphous dispersion and controlled release in the gastrointestinal tract. Additionally, a nano-bio interaction was demonstrated between nanoparticles and a key protein involved in chylomicron assembly; this biochemical reaction in cellular was utilized for the first time to promote lymphatic transport of nanocarriers for oral delivery. As a result, the chylomicron-pretended nanocarrier afforded 10.6-fold higher oral bioavailability compared with free LNV and effectively delivered LNV to gut-associated lymphoid tissues, where HIV persists and actively evolves. This approach not only promises a potential application to HIV-infected individuals but also opens a new avenue to other lymph-mediated pathologies such as autoimmune diseases and lymphatic tumor metastasis.

Pathophysiology of Diabetic Dyslipidemia.

Accumulating clinical evidence has suggested serum triglyceride (TG) is a leading predictor of atherosclerotic cardiovascular disease, comparable to low-density lipoprotein (LDL)-cholesterol (C) in populations with type 2 diabetes, which exceeds the predictive power of hemoglobinA1c. Atherogenic dyslipidemia in diabetes consists of elevated serum concentrations of TG-rich lipoproteins (TRLs), a high prevalence of small dense low-density lipoprotein (LDL), and low concentrations of cholesterol-rich high-density lipoprotein (HDL)2-C. A central lipoprotein abnormality is an increase in large TG-rich very-low-density lipoprotein (VLDL)1, and other lipoprotein abnormalities are metabolically linked to increased TRLs. Insulin critically regulates serum VLDL concentrations by suppressing hepatic VLDL production and stimulating VLDL removal by activation of lipoprotein lipase. It is still debated whether hyperinsulinemia compensatory for insulin resistance is causally associated with the overproduction of VLDL. This review introduces experimental and clinical observations revealing that insulin resistance, but not hyperinsulinemia stimulates hepatic VLDL production. LDL and HDL consist of heterogeneous particles with different size and density. Cholesterol-depleted small dense LDL and cholesterol-rich HDL2 subspecies are particularly affected by insulin resistance and can be named "Metabolic LDL and HDL," respectively. We established the direct assays for quantifying small dense LDL-C and small dense HDL(HDL3)-C, respectively. Subtracting HDL3-C from HDL-C gives HDL2-C. I will explain clinical relevance of measurements of LDL and HDL subspecies determined by our assays. Diabetic kidney disease (DKD) substantially worsens plasma lipid profile thereby potentiated atherogenic risk. Finally, I briefly overview pathophysiology of dyslipidemia associated with DKD, which has not been so much taken up by other review articles.

Bioactive-Chylomicrons for Oral Lymphatic Targeting of Berberine Chloride: Novel Flow-Blockage Assay in Tissue-Based and Caco-2 Cell Line Models.

PURPOSE: To develop novel bioactive-chylomicrons to solve oral delivery obstacles of Berberine chloride and target the lymphatic system. METHODS: Berberine-loaded bioactive-chylomicrons were prepared and underwent full in vitro characterization. Intestinal permeability was appraised via both non-everted gut sac model and Caco-2 cell model. Furthermore, Bioactive-chylomicrons' cellular uptake and distribution were examined by laser scanning confocal microscopy. Finally, a novel chylomicron flow-blockage assay on tissue and cellular levels were elaborated to assess the lymphatic targeting ability. RESULTS: Berberine-loaded chylomicrons showed spherical vesicles of size (175.6 nm), PDI (0.229), zeta potential (-16 .6 mV) and entrapment efficiency (95.5%). Ex-vivo intestinal permeability studies demonstrated 10.5 fold enhancement in permeability of Berberine-loaded chylomicrons over free Berberine. Moreover, Caco-2 studies revealed significant improvement in chylomicrons' permeability and cellular uptake. Furthermore, confocal microscopy analyses revealed 2 fold increase in berberine-loaded chylomicrons' intracellular fluorescence. Lymphatic targeting models were successfully elaborated using cycloheximide protein synthesis inhibitor. Such models demonstrated 47 and 27.5% reduction in ex-vivo and Caco-2 permeability respectively. Finally, a good rank order correlation was established between different permeability assessment techniques. CONCLUSION: The findings shed the light on the underlying mechanisms of Berberine bioavailability improvement. Consequently, berberine-loaded chylomicrons could be considered as promising bioactive-nanocarriers for Berberine lymphatic targeting and bioavailability improvement.

Phytochylomicron as a dual nanocarrier for liver cancer targeting of luteolin: in vitro appraisal and pharmacodynamics.

AIM: A novel luteolin (LUT) loaded dual bionanocarrier 'phytochylomicron' was elaborated to allow LUT injectable delivery and liver cancer targeting. METHODS: LUT-phospholipid complex was prepared and loaded into chylomicron nanocarrier. Then phytochylomicron underwent physicochemical characterization, cell culture and pharmacodynamics studies on a new liver-tumor model. RESULTS: Phytochylomicron showed sustained release pattern with minimum drug leakage until reaching the liver. Cell culture studies showed high growth inhibition of Hep G2 cells with 2.6-fold enhancement in cellular uptake. Pharmacodynamics demonstrated enhanced tumor growth inhibition (sixfold) with a significant tumor size reduction. Finally, cell culture results demonstrated an excellent correlation with pharmacodynamics confirming the obtained findings. CONCLUSION: A novel phytochylomicron nanosystem was successfully elaborated with promising characteristics that promoted injectable LUT delivery and liver cancer targeting. [Formula: see text].

Optimized, Fast-Throughput UHPLC-DAD Based Method for Carotenoid Quantification in Spinach, Serum, Chylomicrons, and Feces.

An improved UHPLC-DAD-based method was developed and validated for quantification of major carotenoids present in spinach, serum, chylomicrons, and feces. Separation was achieved with gradient elution within 12.5 min for six dietary carotenoids and the internal standard, echinenone. The proposed method provides, for all standard components, resolution > 1.1, linearity covering the target range (R > 0.99), LOQ < 0.035 mg/L, and intraday and interday RSDs < 2 and 10%, respectively. Suitability of the method was tested on biological matrices. Method precision (RSD%) for carotenoid quantification in serum, chylomicrons, and feces was below 10% for intra- and interday analysis, except for lycopene. Method accuracy was consistent with mean recoveries ranging from 78.8 to 96.9% and from 57.2 to 96.9% for all carotenoids, except for lycopene, in serum and feces, respectively. Additionally, an interlaboratory validation study on spinach at two institutions showed no significant differences in lutein or ß-carotene content, when evaluated on four occasions.

Apomorphine and its esters: Differences in Caco-2 cell permeability and chylomicron affinity.

Oral delivery of apomorphine via prodrug principle may be a potential treatment for Parkinson's disease. The purpose of this study was to investigate the transport and stability of apomorphine and its esters across Caco-2 cell monolayer and their affinity towards chylomicrons. Apomorphine, monolauroyl apomorphine (MLA) and dilauroyl apomorphine (DLA) were subjected to apical to basolateral (A-B) and basolateral to apical (B-A) transport across Caco-2 cell monolayer. The stability of these compounds was also assessed by incubation at intestinal pH and physiological pH with and without Caco-2 cells. Molecular dynamics (MD) simulations were performed to understand the stability of the esters on a molecular level. The affinity of the compounds towards plasma derived chylomicrons was assessed. The A-B transport of intact DLA was about 150 times lower than the transport of apomorphine. In contrast, MLA was highly unstable in the aqueous media leading to apomorphine appearance basolaterally. MD simulations possibly explained the differences in hydrolysis susceptibilities of DLA and MLA. The affinity of apomorphine diesters towards plasma derived chylomicrons provided an understanding of their potential lymphatic transport. The intact DLA transport is not favorable; therefore, the conversion of DLA to MLA is an important step for intestinal apomorphine absorption.

Recent Advances in Analytical Methods on Lipoprotein Subclasses: Calculation of Particle Numbers from Lipid Levels by Gel Permeation HPLC Using "Spherical Particle Model".

Recently, we developed an analytical method for determining the lipid levels and particle numbers in lipoprotein subclasses covering a wide size range from chylomicrons to small high density lipoproteins, by using gel permeation high-performance liquid chromatography (GP-HPLC). The challenges in analytical methods on lipoprotein subclasses have been addressed from 1980 by Hara and Okazaki using commercial TSK gel permeation columns. Later, the improvements in the hardware, separation and detection of lipoproteins, and the data processing software, using a Gaussian distribution approximation to calculate lipid levels of lipoprotein subclasses, have been extensively utilized in these analytical methods for over thirty years. In this review, we describe on the recent advances in analytical methods on lipoprotein subclasses based on various techniques, and the calculation of particle numbers from lipid levels by GPHPLC using the "spherical particle model". Free/ester ratio of cholesterol in particular lipoprotein subclass was accurately estimated from triglyceride, total cholesterol (free and esterified) and the size of the particle based on this model originally proposed by Shen and Kezdy.

Chylomicrons: Advances in biology, pathology, laboratory testing, and therapeutics.

The adequate absorption of lipids is essential for all mammalian species due to their inability to synthesize some essential fatty acids and fat-soluble vitamins. Chylomicrons (CMs) are large, triglyceride-rich lipoproteins that are produced in intestinal enterocytes in response to fat ingestion, which function to transport the ingested lipids to different tissues. In addition to the contribution of CMs to postprandial lipemia, their remnants, the degradation products following lipolysis by lipoprotein lipase, are linked to cardiovascular disease. In this review, we will focus on the structure-function and metabolism of CMs. Second, we will analyze the impact of gene defects reported to affect CM metabolism and, also, the role of CMs in other pathologies, such as atherothrombotic cardiovascular disease and diabetes mellitus. Third, we will provide an overview of the laboratory tests currently used to study CM disorders, and, finally, we will highlight current treatments in diseases affecting CMs.

Poly-(R)-3-hydroxybutyrates (PHB) are Atherogenic Components of Lipoprotein Lp(a).

The hypothesis is that poly-(R)-3-hydroxybutyrates (PHB), linear polymers of the ketone body, R-3-hydroxybutyrate (R-3HB), are atherogenic components of lipoprotein Lp(a). PHB are universal constituents of biological cells and are thus components of all foods. Medium chain-length PHB (<200 residues) (mPHB) are located in membranes and organelles, and short-chain PHB (<15 residues) are covalently attached to certain proteins (cPHB). PHB are highly insoluble in water, but soluble in lipids in which they exhibit a high intrinsic viscosity. They have a higher density than other cellular lipids and they are very adhesive, i.e. they engage in multiple noncovalent interactions with other molecules and salts via hydrogen, hydrophobic and coordinate bonds, thus producing insoluble deposits. Following digestive processes, PHB enter the circulation in chylomicrons and very low density lipoproteins (VLDL). The majority of the PHB (>70%) are absorbed by albumin, which transports them to the liver for disposal. When the amount of PHB in the diet exceed the capacity of albumin to safely remove them from the circulation, the excess PHB remain in the lipid core of LDL particles that become constituents of lipoprotein Lp(a), and contribute to the formation of arterial deposits. In summary, the presence of PHB ­ water-insoluble, dense, viscous, adhesive polymers ­ in the lipid cores of the LDL moieties of Lp(a) particles supports the hypothesis that PHB are atherogenic components of Lp(a).

Delayed clearance of triglyceride-rich lipoproteins in young, healthy obese subjects.

Obesity is associated with the metabolic syndrome. The aims were, first, to study the postprandial triglyceride clearance in young, healthy obese subjects and, second, to investigate if fasting triglycerides can predict delayed postprandial triglyceride clearance. Eighteen apparently healthy, obese subjects with no clinical signs of metabolic disturbances participated. Controls were age- and sex-matched, healthy, normal weight subjects. Subclinical markers of metabolic disturbances were assessed by measuring postprandial triglycerides in serum and in chylomicrons by oral fat tolerance test. Postprandial triglyceride clearance for 8 h was assessed indirectly as removal of the lipid from serum during the oral fat tolerance test. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Twelve (66%) of the apparently healthy obese individuals had insulin resistance measured by HOMA-IR. There was a delayed clearance of serum triglycerides and chylomicron triglycerides at 6 h when compared with the control group, while, at 8 h, the differences were only detected for the chylomicron triglyceride clearance. Triglyceride response was significantly greater in the obese subjects. Fasting triglycerides in upper normal level predicted a delayed postprandial triglyceride clearance and insulin resistance. In young, apparently healthy obese subjects early metabolic disturbances including insulin resistance and delayed postprandial triglyceride clearance can be detected. Fasting serum triglyceride in upper normal level predicted delayed postprandial triglyceride clearance and insulin resistance.

Biomimetic reassembled chylomicrons as novel association model for the prediction of lymphatic transportation of highly lipophilic drugs via the oral route.

Drug association with isolated natural chylomicrons (nCM) can be used to predict the lymphatic transportation potential of highly lipophilic drugs. However, the nCM model is compromised by inter-group variations in isolated nCM samples and the need to sacrifice a large quantity of animals. In this study, reassembled chylomicrons (rCM) model was set up and evaluated with respect to mimicking the drug association capacity of nCMs. A thin-film dispersion method was used to prepare rCMs, whose compositions consisted of triglycerides, phospholipids, cholesterols and derivatives in a ratio similar to that of nCMs. Partial least squares (PLS) analysis was used to evaluate the influence of molecular descriptors on drug association with CMs and establish multivariable regression equations for prediction of drug association. Chemical descriptors affecting drug association with nCM are in the sequence of hydrogen binding acceptors (HBA)>polar surface area (PSA)>solubility in long-chain triglycerides (SLCT)>logP>melting point (MP)>logD>molar volume (MV)>density>pKa>molar weight (MW)>freely rotatable bonds (FRB)>hydrogen binding donors (HBD). HBA, PSA, HBD, MP, density, pKa, FRB, and HBD were found to reduce the degree of drug association with nCM, whereas all other descriptors increased it. Sequences of chemical descriptors affecting drug association with rCM was in the order of pKa>SLCT>FRB>HBA>MW>MV>HBD>logP>MP>PSA>logD>density. However, the degree of drug association with nCMs was closely correlated to that with rCMs. Drug association with both CMs could be predicted using pre-established equations and PLS. In conclusion, rCMs could be used as substitute for nCMs in prediction of lymphatic transportation of highly lipophilic drugs.

Enhanced association of probucol with chylomicron by pharmaceutical excipients: an in vitro study.

In this study, we examined the effect of pharmaceutical excipients preferred in lipid-based formulations for lymphatic delivery on in vitro association of probucol with chylomicron (CM). CM stability study was performed under the conditions of room temperature, refrigeration and deep freezing to optimize the storage condition of CM dispersion prior to CM-binding study. The mean particle size, size distribution and zeta potential value were considerably maintained for 48 h under the refrigeration condition. CM-binding study was conducted using probucol incorporated in vehicles composed of solubilizer (Transcutol HP or ethanol or propylene glycol) or surfactant (Tween-80 or Tween-20 or Cremophor ELP), and CM dispersion obtained by a density-gradient ultracentrifugation. Levels of the association of probucol with CM were largely governed by solubility of probucol in pharmaceutical excipients tested in this study, and the ability of solubilizers tested to enhance the affinity of probucol with CM was much greater than that of surfactants tested. Furthermore, the association of probucol with CM was enhanced by increasing the amount of the drug solubilized in propylene glycol or Transcutol HP. Together, the result of this CM-binding study showed that solubilizers tested in this study can increase levels of the association of probucol with CM, potentially leading to an increase in lymphatic exposure of drugs. Thus, identifying pharmaceutical excipients having better solubilizing ability would be advantageous for enhanced lymphatic delivery.