Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract
Alex YuJason BakerAnn FiorittoYing WangRuijuan LuoSiwei LiBo WenMichael J. BlyYasuhiro TsumeMark J. KoenigsknechtXinyuan ZhangRobert LionbergerGordon L. AmidonWilliam L. HaslerDuxin Sun
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As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-5-ASA) were measured using LC–MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-5-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products.Keywords:
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Abstract The mucosal surface area of the guinea pig duodenum, jejunum, and ileum was determined during development, in three age groups: 1‐day‐old and 2‐ and 12‐week‐old animals. The morphometric analysis was performed at three magnification levels. The nominal surface area was determined at the macroscopic level, from intestinal length and perimeter. Villus and microvillus amplification factors were estimated at light‐microscopic and transmission electron‐microscopic levels, respectively. We found: (1) an increase in the nominal surface area that is maximal in the ileum (7.7‐fold); (2) an increase in the villus amplification factor in the duodenum (1.4‐fold) and a decline in the jejunum and ileum (0.8‐fold), although in the jejunum villus dimensions rise; and (3) a similar increase in the microvillus amplification factor in the three segments (1.1‐ to 1.4‐fold). In conclusion, the total mucosal surface area increased from day 1 to week 12, by 3‐fold in the duodenum and jejunum and by 8‐fold in the ileum. Regionally, the jejunum shows the largest mucosal surface area, followed by the ileum, and, finally, the duodenum. Microsc. Res. Tech. 63:206–214, 2004. © 2004 Wiley‐Liss, Inc.
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In the study,small intestinal mucosal structure,muscular layer thickness and the distributions and numbers of intraepithelial lymphocytes(IELs) and goblet cells(GCs) from Sunit sheep at 6 months old age was determined by Histological and Histochemical methods.The results showed the length of Duodenum villus were the longest,its length attained(353.25±60.48) μm,the Jejunum and Ileum in villus length were(317.27±72.02) μm and(275.36±47.62) μm respectively,but there was markedly different between Jejunum and Ileum(P0.05);In mucosal thickness,Duodenum were the thickest reaching(669.15±139.04) μm,the Jejunum and Ileum were(586.72±134.50) μm and(551.85±91.32) μm,Duodenum in thickness was extremely different comapared with that of the Ileum and Jejunum(P0.01);In the thickness of muscular layer,Ileum was the thickest reaching(280.45±58.33) μm,Jejunum was(167.16±42.63) μm and Duodenum was(148.78±38.36) μm,the difference was marked among them(P0.01);In the depth of crypt,Duodenum was the deepest reaching(309.36±74.21) μm,Jejunum was(286.23±57.23) μm,the difference was marked among them(P0.01);In the value of V/C,Duodenum and Jejunum were(1.80±0.45) and(2.00±0.48) respectively,there was different between Jejunum and Ileum(P0.01);In the number of IELs and GCs,all parts of intestinal mucosal layer were not significantly different(P0.05).The conclusion could be made that the length of villus,the mucosal thickness and the depth of crypt were gradually become smaller,while the muscular layer thickness were gradually become greater in small intestine from anterior to posterior,but there were no change of IELs and GCs numbers in all parts of small intestine.
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Intraepithelial lymphocyte
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This study has quantified, for the first time, the relative levels of neuromedin U (NmU) mRNA in the rat gastrointestinal tract using Northern blot analysis. NmU message was detected in all regions of the gastrointestinal tract from the oesophagus to the rectum. The greatest levels were found in the duodenum and jejunum, the principal sites for absorption, which were 2.5- and 3-fold respectively above ileal levels. Quantification of NmU mRNA and peptide contents in the duodenum, jejunum and ileum during postnatal development of the rat showed message and peptide levels to be greater in the maturing rat than in neonates. Message levels in the duodenum, jejunum and ileum showed 14-, 7- and 4-fold increases respectively between 1 and 56 days after birth, whilst the corresponding peptide levels in the duodenum, jejunum and ileum showed 33-, 14- and 25-fold increases respectively. Food deprivation caused a small, but significant, decrease in message levels in the jejunum and colon, but there was no change in the duodenum or ileum. This shows that the presence of food has little effect on NmU mRNA levels in the gut.
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The objective of this study was to investigate the development of the weight and the morphological development of the small intestine in Yangzhou geese. The weight, length and perimeter of the small intestine, height and width of the villi, depth of the crypts were measured when geese were 1, 14, 28, 42, 56 and 70 days of age. The results revealed that the weight of the duodenum, jejunum, and ileum (relative to the BW) increased, peaked on day 14 and tended to decline thereafter with age. The weight of the duodenum, jejunum, and ileum (relative to the BW) kept steady-going on 56, 42, 42 days, respectively. A 3-fold increase in length and 2-fold increase in perimeter for the three segments during the period were obtained. The duodenum increased little in length, whereas both jejunum and ileum increased 2 and 3-folds from 1 to 70 days examined. The increase in perimeter of the duodenum, jejunum and ileum was greater from day 1 to 14 than from day 14 to 28. The length and perimeter of the intestinal segments of the gastro-intestinal of Yangzhou geese (relative to the BW) peaked on day 1, then decreased with age and kept steady-going on 42 days, except the relative perimeter of the duodenum. The villus height, surface area and crypt depth in the small intestine were positively correlated with the age of the geese. The ratio of the villus height to the crypt depth (V/C) differed among the segments of the small intestine and at the different time points. The V/C in the ileum increased from day 1 to 70, whereas in the duodenum the ratio first decreased, then rose and descended. However, in the jejunum the ratio increased first, then dropped and rose again, and descended eventually. Key words : Geese, small intestine, morphology.
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The objective of this study was to investigate the difference of mRNA expression of cationic amino acid transporter rBAT(system b0,+),y+LAT2(system y+L),CAT1(system y+)and CAT4(system y+) in different intestinal segments of chicken by relative quantitative RT-PCR.Yellow covered chickens at age of 30 days were used and the different intestinal segments were collected.The result showed: rBAT and y+LAT2 mRNA abundance in colorectum were significant lower than that of duodenum,jejunum and ileum(P0.01).rBAT and y+LAT2 mRNA expression in ileum were higher than in duodenum and jejunum,but had no significant difference among them(P0.05);The expression of CAT1 mRNA in colorectum was very significantly higher than that of duodenum,jejunum and ileum(P0.01).Expression abundance in ileum was higher than in jejunum significantly(P0.01) and higher than duodenum by 27.9 %(P=0.111).Same as CAT1 mRNA,the expression of CAT4 mRNA in colorectum was higher than that of duodenum,jejunum and ileum significantly(P0.01);There was no difference among duodenum,jejunum and ileum(P0.05).The result indicates that the tissue-specific of transporter mRNA expression of cationic amino acid transporter system b0,+ and system y+LAT2 are similar and discriminated with that of system y+.
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Amino acid transporter
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To study the effect of circulation small peptides concentration on mRNA expression in small intestine, graded amount of soybean small peptides (SSP) were infused into lactating goats through duodenal fistulas. Peptide-bound amino acid (PBAA) concentration in arterial plasma and the mRNA expression of PepT1 was detected in the current study. The results showed that concentrations of all peptidebound amino acids (PBAA) increased and the activity of PepT1 in duodenum tissue was enhanced by SSP infusion. The PepT1expression in duodenum tissue was significantly increased with the increment of amounts of SSP infusion (P<0.05). That in ileum tissue was increased with the increment of the amounts of SSP infusion; the increment of Pep T1 expression was significant only in the 180 g/d treatment (P<0.05). mRNA abundance of PepT1 in jejunum tissue was 1.1 to 1.8 to 2.4 times in SSP infusion group as compared with the control group. In the 120 and 180 g/d treatment, the difference of PepT1 expression in jejunum was significant (P<0.05). The data suggested Pep T1 expression in duodenum, ileum and jejunum tissue was enhanced by an increase in circulation small peptide concentration, and the duodenum might be a main position of small peptides absorption in intestine.
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Summary The intestinal morphology of 7‐week‐old pigs was investigated by light (LM) and scanning electron microscopy (SEM). The piglets were fed either a semisynthetic or a cereal‐based diet. The shapes of the intestinal villi and crypts of the duodenum, jejunum and ileum were examined. The villi were predominantly tongue‐shaped. In the duodenum they were also ridged, branched and folded, and in the jejunum they were also leaf‐like and ridged. At places with lymph follicles, the surface of the ileum was rugged with meandering fold‐like villi. The crypts of the three segments of the small intestine were mainly coiled and sometimes branched. A novel morphometric evaluation method was introduced using the enlargement factors of each villus and crypt surface. The enlargement factor for the villus surface of the duodenum, jejunum and ileum was 3.13, 3.72 and 2.71, respectively. The factor for the crypt surface of the duodenum, jejunum and ileum was 9.07, 8.94 and 6.53, respectively. Furthermore, the relative proliferation rate and the epithelial renewal index were calculated for the first time. The relative proliferation rate of the duodenum, jejunum and ileum was 32.88, 34.78 and 50.77 proliferations per mm crypt perimeter, respectively. The diets consumed had an influence on the epithelial renewal index being higher for piglets fed the cereal‐based diets.
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In order to study the number changes of mucosal immunityassociated cells in small intestine of goats which naturally infected by Moniezia benedeni(contract group),the distribution and number of intraepithelial lymphocytes(IELs),plasma cells,goblet cells and eosinophile granulocytes(EOS)were investigated by the histological and histochemical methods,and then compared with control group.The results showed that the number of these four kinds of cells in the contracted group were all significantly higher than control group,and the increased rate of IELs was 169.11% in duodenum,230.38% in jejunum and 233.42% in ileum(P0.01),the increased rate of EOS was 116.78% in duodenum,123.87% in jejunum and 164.51% in ileum(P0.01),the increased rate of plasma cells was 127.34% in duodenum,72.97% in jejunum and 328.26% in ileum(P0.01),the increased rate of goblet cells was 33.40% in duodenum,41.42% in jejunum and133.17% in ileum.In addition,the number of IELs and goblet cells all decreased substantially from duodenum to ileum in both contracted and control groups,otherwise,the number of EOS increased from duodenum to ileum in two groups,and the number of plasma cells increased from duodenum to ileum in contracted group only but increased from duodenum to jejunum and decreased from jejunum to ileum in control group.Besides,the number of these four kinds of cells had obvious differences in the all small intestine of control group(P0.01);The number of goblet cells,plasma cells and EOS also had obvious differences in the all small intestine of contracted group(P0.01),but the number of IELs only had difference in jejunum and ileum(P0.05).The results suggested that the cellular and humoral immunity function were respectively increased trough the proliferation of IELs and plasma cells which were special mucosal immunity-associated cells,and also trough the proliferation of non-special mucosal immunity-associated cells(EOS and goblet cells)enhanced the anti-infection.It is thus clear that goat could strength the local immune function by the proliferation of relative cells to monitor the immune escape of parasite.
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Intraepithelial lymphocyte
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1. Thirty-five pigs were fitted with single re-entrant cannulas in either the duodenum, jejunum or ileum. A further twenty-four pigs were used in a conventional digestibility trial. 2. Methods for collecting, sampling and returning digesta were developed. 3. A 'practical-type' diet and two purfied diets were used, fed twice daily. 4. Flow and pH of digesta were measured hourly in the duodenum and jejunum, and every 6 h in the ileum. 5. In the duodenum and jejunum there were clear flow responses to feeding, while such an effect was not found in the ileum where the flow-rate was much lower and more uniform than in the former sites. 6. In the duodenum and jejunum, and within 6 h periods in the ileum, there was considerable variation in the flow-rate between different pigs within each hour but there was less variation in pH. 7. The pattern of flow in the duodenum and jejunum was similar for each of the diets but the total flow and the average pH in 24 h differed significantly between diets. There were more digesta of a lower pH from the 'practical-type' diet than the purified diets. 8. The pH in the duodenum was highest after feeding and decreased with increasing time after feeding. In the jejunum and ileum the pH-varied over a much smaller range than in the duodenum. 9. Collections for 6 h periods appeared to be insufficiently long to predict the values obtained in 24 h collections with reasonable accuracy.
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Digestion
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