Intestinal Absorption Rate Research Articles

Establishment of a Novel In Situ Rat Model for Direct Measuring ofIntestinal Drug Absorption: Confirmation of Inhibitory Effects of Daijokito onthe Absorption of Ranitidine

Daijokito (DJKT), a classical traditional Kampo and Chinese medicine, has been used to treat acute pancreatitis in China. In our previous study, DJKT was found to reduce the area under the plasma concentration-time curve (AUC) of ranitidine in humans. Therefore, we established a novel rat model to examine the direct absorption of ranitidine after daijokito administration. An in situ intestinal injection with portal vein sampling (IIPS) model was created to determine the rate of intestinal drug absorption. Rats were divided into two groups: the ranitidine group (R, n = 6) or the ranitidine and daijokito group (RD, n = 6). Blood was collected after intestinal injection of drugs. After the experiment, the concentrations of ranitidine were measured by LC/MS/MS analysis. The concentrations of ranitidine increased linearly with time in both groups. Compared with the R group, the concentrations of ranitidine in RD group significantly decreased throughout the experiment. Co-administration of ranitidine with DJKT resulted in significant decreases in intestinal absorption in rats. The reduction of the systemic ranitidine concentration by co-administration of DJKT may be due, at least in part, to the inhibition of intestinal absorption of ranitidine.

PP.12.20] ANTIANGIOGENIC CYSTEINE-KNOT MINIPROTEINS PRESENT IN TOMATO FRUITS AND INDUSTRIAL DERIVATIVES CAN BE ABSORBED THROUGH THE GASTROINTESTINAL MUCOSA

Objective: Tomato fruit is rich in compounds with potential biological activities. We previously identified in tomato fruit two cystine-knot miniproteins (TCMP-1 and -2) endowed with antiangiogenic activities (Cavallini Br J Pharmacol 2011). We tested purified TCMPs (200 nmol/L) on human umbilical vein endothelial cells (HUVEC) migration, a critical step in the angiogenesis. The scratch assay showed that TCMP-2 inhibits by 50% the increase in cell migration induced by VEGF-A. TCMP-2 inhibited VEGFR2 phosphorylation and reduced NO release in HUVEC by 34%. TCMPs inhibited the formation of subintestinal vessels in zebrafish embryos that is controlled by VEGF (Treggiari Mol Nutr Food Res 2015). The present study aimed at defining the pharmacological potential of TCMPs by assessing their oral bioavailability, and estimating the potential dietary intake determining TCMPs concentration in tomato fruits and derivatives. Design and method: We investigated whether TCMPs are absorbed by gastrointestinal apparatus and endure industrial processing without losing their biological activity. The resistance of TCMPs extracted from mature fruits to proteolytic attack was studied in vitro testing simulated gastrointestinal fluids. To explore the intestinal transport of TCMPs we used the differentiated Caco-2 cells model. Finally, we developed a method for purifying TCMPs from tomato paste to assess the effects of the industrial processing on TCMPs biochemistry and bioactivity. Results: The gastric proteases did not produce TCMP fragmentation, indicating that the purified TCMP is resistant to gastro-intestinal proteases. After 24 h incubation, 37.73 ± 9.34% of TCMPs crossed the epithelium, without altering the integrity of the Caco-2 cell layer. We found appreciable amounts of TMCs in different tomato varieties (48.89 ± 0.07 to 61.68 ± 0.07 mg/g FW) and tomato paste. Conclusions: In conclusion, besides the effects of lycopene and other tomato antioxidants, TCMPs may exert beneficial effects for disease prevention and treatment such as diabetic retinopathy, which is characterized by aberrant formation of vessels, caused by enhanced migration of endothelial cells. The strong resistance to gastric and intestinal proteolysis and the high rate of intestinal absorption of TCMPs offer opportunities for oral administration.

Short Bowel Syndrome

Objectives and Study: Intestinal failure (IF) is a state of severe intestinal malabsorption requiring parenteral nutrition (PN) for survival. The leading cause of IF is short bowel syndrome (SBS). This study aims to show whether the presence of the colon makes a difference in children with SBS, and to find correlations between intestinal absorption rate, citrulline level, anatomy of the remnant bowel and parenteral nutrition dependency. Methods: Twenty-three SBS children were included in this study and divided into two groups according to the presence or absence of the colon. Bowel length, citrulline plasma levels, intestinal absorption rate [by using three days stool balance analysis] and PN dependency index [by using the index Non Protein Energy Intake (NPEI)/Resting Energy Expenditure (REE) by Schofield formula], were assessed. Regression analysis and student t tests comparing variables were performed. Results: Patients with colon (n=14) had significantly shorter remnant small bowel as compared with those without colon (n=9) (29.25 ± 25.64 vs. 60.88 ± 22.54 cm; P < 0.003) and lower fecal sodium losses (48.5 ± 28.07 vs. 85.88 ± 18.98 mmol/l; P < 0.002). No difference was found between the groups for the percentage energy absorption (63.4 ± 19.0 vs 66.4 ± 15.4% respectively), while citrulline plasma levels showed only a tendency to be higher in SBS without colon (19.1 ± 12.17 vs. 14.4 ± 9.72 μmol/l; P = 0.17). PN dependency was not significantly different between neither groups, nor the total energy intake from oral or enteral nutrition. No correlation was found between the different parameters, although the citrulline level correlates with the small bowel length in the group with colon (r2 = 0.57). Conclusion: By using three days’ stool balance analysis, this study demonstrates for the first time in SBS children, the role of the colon in energy salvage in addition to water- electrolytes absorption. It emphasizes the importance of early restoration of intestinal continuity and preservation of intestinal microbiota.

Influence of autoclave treatment and enzymatic hydrolysis on the antioxidant activity of Opuntia ficus-indica fruit extract.

The objectives of this study were to obtain Opuntia ficus-indica fruit (OFIF) extract by autoclave treatment, to convert the flavonoid glycosides in the autoclave extract (AE) to aglycones by enzymatic hydrolysis, and to compare the antioxidant activity of AE and OFIF extracts obtained by other conventional methods. It was revealed that the total polyphenol and flavonoid content and antioxidant activity of AE were higher than those of water extract but were a slightly lower than those of ethanol extract, which indicates that autoclave treatment might be an efficient extraction method for OFIF. Moreover, it was confirmed that the conversion of various flavonoid glycosides to aglycones in all the OFIF extracts does not significantly affect the antioxidant activities. Therefore, it is extrapolated that the antioxidant activity might be correlated to the intestinal absorption rates and metabolic pathway induction upon oral administration rather than the structure of compound itself.

Angubindin-1, a novel paracellular absorption enhancer acting at the tricellular tight junction

A limiting barrier for mucosal absorption of drugs is the tight junction (TJ). TJs exist between two adjacent cells (bicellular TJ, bTJ) and at the sites where three cells meet (tricellular TJ, tTJ). We present a novel approach which employs a physiologically regulated pathway for the passage of large molecules through the tTJ. Main barrier-relevant tTJ proteins are tricellulin and angulin-1 to -3. We developed an angulin binder from Clostridium perfringens iota-toxin (Ib) whose receptor is angulin-1. An Ib fragment corresponding to amino acids 421–664 (Ib421-664) of iota-toxin proved to bind in cells expressing angulin-1 and -3, but not angulin-2. This binding led to removal of angulin-1 and tricellulin from the tTJ which enhanced the permeation of macromolecular solutes. Ib421-664 enhanced intestinal absorption in rats and mice. Our findings indicate that Ib421-664, which we designate angubindin-1, is a modulator of the tTJ barrier and that modulation of that barrier qualifies for a new strategy of developing a mucosal absorption enhancer.

How to assess the efficacy of phosphate binders

Background and aimsThe efficacy of phosphate binders is difficult to be estimated clinically. This study analyzes the changes in serum phosphate and urinary phosphate excretion after the prescription of phosphate binders (PB) in patients with chronic kidney disease stage 4–5 pre-dialysis, and the usefulness of the ratio between total urinary phosphate and protein catabolic rate (Pu/PCR) for estimating the efficacy of PB. MethodsThis retrospective observational cohort study included adult chronic kidney disease patients. Biochemical parameters were determined baseline and after 45–60 days on a low phosphate diet plus PB (“binder” subgroup=260 patients) or only with dietary advice (“control” subgroup=79 patients). ResultsPhosphate load (total urinary excretion) per unit of renal function (Pu/GFR) was the best parameter correlated with serum phosphate levels (R2=0.61). Mean±SD level of Pu/PCR was 8.2±2.3mg of urinary phosphate per each g of estimated protein intake. After treatment with PB, serum phosphate levels decreased by 11%, urinary phosphate 22%, protein catabolic rate 7%, and Pu/PCR 15%. In the control subgroup, Pu/PCR increased by 20%. Urinary phosphate and urea nitrogen excretion correlated strongly, both baseline and after PB or dietary advice. ConclusionsThe proposed parameter Pu/PCR may reflect the rate of intestinal phosphate absorption, and therefore, its variations after PB prescription may be a useful tool for estimating the pharmacological efficacy of these drugs.

Cómo estimar la eficacia de un captor del fósforo

Background and aimsThe efficacy of phosphate binders is difficult to be estimated clinically. This study analyzes the changes in serum phosphate and urinary phosphate excretion after the prescription of phosphate binders (PB) in patients with chronic kidney disease stage 4-5 pre-dialysis, and the usefulness of the ratio between total urinary phosphate and protein catabolic rate (Pu/PCR) for estimating the efficacy of PB. MethodsThis retrospective observational cohort study included adult chronic kidney disease patients. Biochemical parameters were determined baseline and after 45-60 days on a low phosphate diet plus PB (“binder” subgroup=260 patients) or only with dietary advice (“control” subgroup=79 patients). ResultsPhosphate load (total urinary excretion) per unit of renal function (Pu/GFR) was the best parameter correlated with serum phosphate levels (R2=0.61). Mean±SD level of Pu/PCR was 8.2±2.3mg of urinary phosphate per each g of estimated protein intake. After treatment with PB, serum phosphate levels decreased by 11%, urinary phosphate 22%, protein catabolic rate 7%, and Pu/PCR 15%. In the control subgroup, Pu/PCR increased by 20%. Urinary phosphate and urea nitrogen excretion correlated strongly, both baseline and after PB or dietary advice. ConclusionsThe proposed parameter Pu/PCR may reflect the rate of intestinal phosphate absorption, and therefore, its variations after PB prescription may be a useful tool for estimating the pharmacological efficacy of these drugs.

Update on recent progress in vitamin D research. Eldecalcitol and intestinal calcium absorption.

Though various physiological actions have been attributed to vitamin D, its most important function is to promote absorption of calcium from the intestinal tract. While the absorption rate of calcium is generally low, it tends to decline further with age. In addition, calcium intake is decreasing in recent years in Japan. Therefore, it is important to increase the intestinal calcium absorption rate. Eldecalcitol has been shown to increase calcium absorption from the intestinal tract, suppress bone resorption, increase bone mineral density, and prevent fractures. Elocalcitol use leads to a lower systemic active vitamin D[1α,25(OH)2D]concentration, compared to that with alfacalcidol use. This is because eldecalcitol inhibits vitamin D activation in the kidney. Therefore, it is presumed that the calcium absorption-boosting effect of eldecalcitol is not due to the action of 1α, 25(OH)2D, but due to eldecalcitol itself.

Calcium and phosphorus metabolism and nutrition of poultry: are current diets formulated in excess?

Calcium (Ca) and phosphorus (P) are important nutrients in poultry diet formulations. In the present review, we discuss recent advances in our understanding of the metabolism of Ca and P in poultry. Recent data are provided in support of the proposition that current poultry diets are formulated in excess for Ca and P. The quantities of Ca and P available for metabolism reflect rates of intestinal absorption, bone accretion and resorption, glomerular filtration, renal tubular reabsorption, and intestinal endogenous losses. Ca and P homeostasis is largely under endocrine control. Parathyroid hormone and the hormonal form of vitamin D3 are the two hormones credited with this role. However, a novel hormonal axis involving Fibroblast Growth Factor 23 and Klotho has been recently delineated, which, in conjunction with parathyroid hormone and vitamin D3, tightly regulates Ca and P homeostasis. Recent studies have suggested that current commercial diets for both broilers and layers contain excess Ca and P, the content of which could be reduced without affecting production or bird welfare. The challenge in reducing Ca and P concentrations in poultry diets is the uncertainty about what concentrations of Ca and P can be fed without compromising bird welfare. This is because there are limited data on the available P and Ca concentrations in poultry feedstuffs determined biologically. This is further complicated by the need for agreement on evaluation systems for evaluation of Ca and P bioavailability. We conclude that direct ileal or pre-caecal digestible Ca and P values are preferred.

Effect of dietary supplementation of fermented Rhus verniciflua on growth performance, apparent total tract digestibility, blood profile, and fecal microflora in weanling pigs

Fermented Rhus verniciflua (FRV) as feed additives act as excellent anti-diarrheal drugs as they increase the intestinal absorption rate therefore being indirectly associated with enhancing growth performance and increasing digestibility in livestock. A total of 80 weaned pigs with an average initia...

Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes.

In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon-like peptide-1 (GLP-1) secretion. We evaluated the effects of metformin on serum 3-O-methylglucose (3-OMG; a marker of glucose absorption) and plasma total GLP-1 concentrations during a standardized intraduodenal infusion of glucose and 3-OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double-blind, randomized, crossover design (14 days' washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3-OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3-OMG ( P < .001) and higher plasma total GLP-1 ( P = .003) concentrations. The increment in plasma GLP-1 after metformin vs placebo was related to the reduction in serum 3-OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP-1 secretion in type 2 diabetes.

Effects of 2 Polyoxyethylene Alkyl Ethers on the Function of Intestinal P-glycoprotein and Their Inhibitory Mechanisms

The purpose of this study was to investigate the effects of polyoxyethylene 10-oleyl ether and polyoxyethylene 9-lauryl ether, 2 polyoxyethylene alkyl ethers, on the transport and absorption of 2 P-glycoprotein (P-gp) substrates, quinidine and prednisolone, across the intestinal membrane and to elucidate the inhibitory mechanisms of intestinal P-gp by these polyoxyethylene alkyl ethers. For in vitro studies, we used a diffusion chamber method and the Caco-2 cell model. An in situ closed-loop method was used for in vivo study. The 2 polyoxyethylene alkyl ethers, nonionic surfactants, increased the intestinal absorptive transport of quinidine and prednisolone in the diffusion chamber studies, and absorptive permeability was enhanced in the in vitro Caco-2 cell study. Furthermore, these surfactants enhanced the rat intestinal absorption of prednisolone, and we observed no intestinal membrane damage in the presence of these surfactants. Furthermore, these surfactants increased membrane fluidity in intestinal brush border membranes and inhibited P-gp ATPase activity. For in vitro and in vivo studies, these surfactants enhanced the intestinal absorption of quinidine and prednisolone, 2 P-gp substrates. The alteration in intestinal membrane fluidity and the inhibition of P-gp ATPase activity by these 2 polyoxyethylene alkyl ethers may be confirmed as mechanisms of P-gp inhibition.

Simultaneous Determination of Procaspase Activating Compound 1 and Permeability Markers in Intestinal Perfusion Samples and Application to a Rat Intestinal Absorption Study

A sensitive and simple HPLC method for simultaneous determination of PAC-1 (first procaspase-activating compound), phenol red, and permeability markers (carbamazepine and furosemide) in perfusion samples was developed and validated to assess intestinal absorption of PAC-1 using single-pass intestinal perfusion technique (SPIP) in rats. The chromatographic separation was carried out on a Kromasil C18 column (150 mm × 4.6 mm, 5 μm) with acetonitrile–methanol–30 mmol L−1 phosphate buffer (pH 3.0, 25:10:65, v/v/v) as mobile phase at a flow rate of 1.0 mL min−1, and the wavelength of the UV detector was set at 281 nm. The calibration curves were linear in the ranges of 2.40–48.0 μg mL−1 for PAC-1; 3.60–72.0 μg mL−1 for carbamazepine; 3.20–64.0 μg mL−1 for furosemide, and 4.80–96.0 μg mL−1 for phenol red (r > 0.999). Both the intra- and inter-day precisions (RSD%) of all analytes were less than 6.8 % at three concentration levels, while accuracy ranged from 95.4 to 104.5 %. Data obtained in all method validation studies indicated that the method was suitable for the intended purpose. The effective permeability values (Peff) considering water flux with the help of non-permeable marker phenol red was calculated to be 0.42 × 10−4, 0.62 × 10−4, 0.32 × 10−4 cm s−1 for PAC-1; 0.72 × 10−4, 0.77 × 10−4, 0.52 × 10−4 cm s−1 for carbamazepine; 0.20 × 10−4, 0.16 × 10−4, 0.12 × 10−4 cm s−1 for furosemide in duodenum, jejunum and ileum, respectively. The Peff value can be increased by co-perfusion with verapamil, indicating that absorption of PAC-1 is efficiently transported by P-glycoprotein (P-gp) in the gut wall.

Whey protein hydrolysates enhance water absorption in the perfused small intestine of anesthetized rats.

We evaluated the effect of whey protein hydrolysates (WPH) on the water absorption rate in the small intestine using a rat small intestine perfusion model. The rate was significantly higher with 5g/L WPH than with 5g/L soy protein hydrolysates or physiological saline (p < 0.05). WPH dose-dependently increased the water absorption rate in the range of 1.25-10.0g/L. WPH showed a significantly higher rate than an amino acid mixture whose composition was equal to that of WPH (p < 0.05). The addition of 4-aminomethylbenzoic acid, an inhibitor of PepT1, significantly suppressed WPH's enhancement of water absorption (p < 0.05). The rate of water absorption was significantly correlated with that of peptides/amino acids absorption in WPH (r = 0.82, p < 0.01). These data suggest that WPH have a high water absorption-promoting effect, to which PepT1 contributes.

Size-exclusive effect of nanostructured lipid carriers on oral drug delivery

Nanostructured lipid carriers (NLCs) are generally recognized as safe (GRAS) to form a controlled nanostructure are a new generation of lipid nanoparticles. In addition to formulation and particle surface properties, particle size had great influence for overcoming gastrointestinal (GI) barriers on the oral drug delivery of lipid based nanoparticles. In the present study, we investigated the effect of size on oral drug delivery for NLCs. The NLCs with different particle sizes (NLCs100nm, NLCs200nm and NLCs300nm) were prepared by using solvent evaporation method and the coumarin-6 (C6) or DiO/DiI was loaded in the nanoparticles as the fluorescence probe. The MTT assay indicated that both blank NLCs and C6-loaded NLCs displayed relatively low toxicity towards Caco-2 cells. Cellular uptake mechanisms of NLCs with different sizes were found to be similar and governed by active endocytosis, clathrin- and caveolae-mediated process. However, the smaller nanoparticle (NLC⿿100nm) showed higher uptake efficiency in Caco-2 cell (P<0.05) as well as higher permeation ability in Caco-2 cell monolayer (P<0.01), compared with NLC⿿200nm and NLC⿿300nm. The fluorescence resonance energy transfer (FRET) assay indicated that all of three NLCs could maintained the structural integrity in blood circulation after oral administration. NLC⿿100nm exhibited the most stability according to the most stable FRET signal. In situ rat intestinal absorption experiments and in vitro ligated rat intestinal loops model demonstrated that all NLCs could rapidly penetrate duodenum versus jejunum, ileum and colon (P<0.01). Moreover, pharmacokinetic studies showed that NLC⿿100nm exhibited highest Cmax and AUC compared with the other two NLCs. In conclusion, the size of 100nm might be the most suitable size for oral drug delivery of lipid based nanoparticles.

Reduced Burst Release and Enhanced Oral Bioavailability in Shikimic Acid–Loaded Polylactic Acid Submicron Particles by Coaxial Electrospray

In this study, using the coaxial electrospray method, we prepared submicron particles of the water-soluble drug shikimic acid (SA) with polylactic acid (PLA) as a polymer, to reduce the burst release and enhance the oral bioavailability. In vitro release study performed in HCl solution (pH 1.2) showed that the coaxial electrospray submicron particles could reduce burst release effect and presented a sustained release profile, compared with free SA and the particles prepared by electrospray method. The absorption of SA in the intestinal tract, studied using an in situ perfusion method in rats, also revealed jejunum as the main absorptive segment followed by duodenum and ileum. Moreover, the SA-loaded particles greatly enhanced the absorption of SA in the tested intestinal segments. The intestinal absorption rate was not enhanced with increasing drug concentration (5-15 μg/mL) which suggested that active transport or facilitated diffusion could play vital role in SA absorption. In addition, the SA-loaded PLA coaxial electrospray particle exhibited a prolonged plasma circulation with enhanced bioavailability after oral administration. In all, the coaxial electrospray technique could provide notable advantages for the oral delivery of SA, thereby enhancing its clinical application.

P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate

The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity.

LC–MS/MS determination and interaction of the main components from the traditional Chinese drug pair Danshen–Sanqi based on rat intestinal absorption

The Chinese drug pair Danshen (Salvia miltiorrhiza)-Sanqi (Panax ginseng) has been widely used for centuries treating various cardiovascular disorders, among which salvianlic acid B (SAB), ginsenoside Rg1 (GRg1 ), ginsenoside Rb1 (GRb1 ) and notoginsenoside R1 (NGR1 ) were identified as the major components. The present study focused on the interaction between these components based on investigating their intestinal absorption using the Ussing chamber technique. The concentrations of SAB, GRg1 , GRb1 and NGR1 in the intestinal perfusate were determined by LC-MS/MS method, followed by Q (accumulative quantity) and Papp (apparent permeability). The results showed that all these four main components displayed very low permeabilities, which implied their poor absorption in the rat intestine. The intestinal absorption level of SAB displayed regioselectivity: duodenum < jejunum < ileum. However, there was no significant difference in the absorption of GRg1 and GRb1 in the different segments. The Q and Papp values of the four main components were obviously increased in jejunum when co-administrating Danshen extract with Sanqi extract. In conclusion, compatibility of Danshen and Sanqi could remarkably improve the intestinal absorption level of the main components in the pair. To some extent, this might explain the nature of the compatibility mechanisms of composite formulae in TCMs.

Mucosal and blood-brain barrier transport kinetics of the plant N-alkylamide spilanthol using in vitro and in vivo models

BackgroundN-alkylamides (NAAs) are a large group of secondary metabolites occurring in more than 25 plant families which are often used in traditional medicine. A prominent active NAA is spilanthol. The general goal was to quantitatively investigate the gut mucosa and blood-brain barrier (BBB) permeability pharmacokinetic properties of spilanthol.MethodsSpilanthes acmella (L.) L. extracts, as well as purified spilanthol were used to investigate (1) the permeation of spilanthol through a Caco-2 cell monolayer in vitro, (2) the absorption from the intestinal lumen after oral administration to rats, and (3) the permeation through the BBB in mice after intravenous injection. Quantification of spilanthol was performed using a validated bio-analytical UPLC-MS2 method.ResultsSpilanthol was able to cross the Caco-2 cell monolayer in vitro from the apical-to-basolateral side and from the basolateral-to-apical side with apparent permeability coefficients Papp between 5.2 · 10−5 and 10.2 · 10−5 cm/h. This in vitro permeability was confirmed by the in vivo intestinal absorption in rats after oral administration, where an elimination rate constant ke of 0.6 h−1 was obtained. Furthermore, once present in the systemic circulation, spilanthol rapidly penetrated the blood-brain barrier: a highly significant influx of spilanthol into the brains was observed with a unidirectional influx rate constant K1 of 796 μl/(g · min).ConclusionsSpilanthol shows a high intestinal absorption from the gut into the systemic circulation, as well as a high BBB permeation rate from the blood into the brain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1159-0) contains supplementary material, which is available to authorized users.

The extra-phosphate intestinal load from medications: is it a real concern?

Reduction of intestinal load of phosphorus is important for the prevention and treatment of chronic kidney disease (CKD)-mineral and bone disorder (MBD). However, this strategy is limited by patients' poor adherence to dietary prescription and by the existence of hidden sources of phosphorus. In addition to food containing phosphate-based additives, it was recently claimed that medications may contribute to increase the load of phosphate (P), mainly present as an excipient. To identify medications containing P as an excipient, we performed a systematic screening of medications which could potentially be prescribed for chronic oral therapies in CKD patients. We examined 311 active pharmaceutical ingredients (APIs) and 3763 branded or generic medications, identified by the anatomical therapeutic chemical (ATC) international classification system. Sixty APIs (19.3%) included at least one medication containing P as an excipient. In total, 472 medications (12.5%) listed P as an excipient. The prevalence of medications containing phosphate as an excipient was highest for oral antidiabetic medications (23.8%), followed by antidepressant (19.2%), antihypertensive (17.5%) and gastro-intestinal tract (16.4%) medications. All other classes showed a prevalence <10%. Within each ATC class, the APIs at risk of containing phosphate were identified as well as the prevalence of both branded and generic medications. Calcium hydrogen phosphate was the most prevalent form (77.7%) of phosphate as an excipient. Our results suggest that the prevalence of phosphate-containing medications is quite low and it is possible to identify, within each drug category, the medications containing P as an excipient. Calcium phosphate, the most prevalent form, has a lower rate of intestinal absorption than sodium phosphate salts. We did not measure the actual P content, but existing data (measured or estimated) show that it is generally low, except for a few medications that can be easily identified. Thus, the extra-phosphate load from medications may be of concern only in special cases, which could be further limited when correct information and prescriptions are given. The extra-phosphate load from P-containing food and beverages remains the main concern of hidden phosphorus sources in CKD patients.