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At least 253 records · Page 14Linked to original sources

PubMed1999

Impact of regional intestinal pH modulation on absorption of peptide drugs: oral absorption studies of salmon calcitonin in beagle dogs.

PURPOSE: To investigate the relationship between the modulation of intestinal pH and the oral absorption properties of a model peptide drug, salmon calcitonin (sCT), in conscious beagle dogs. METHODS: Studies were performed to characterize the disintegration of the formulation, intestinal pH changes, and the appearance of the peptide in the blood. Enteric-coated formulations containing sCT and various amounts of citric acid (CA) were tethered to a Heidelberg capsule (HC) and given orally to normal beagle dogs. Blood samples were collected and analyzed by radioimmunoassay (RIA). Intestinal pH was continuously monitored using the Heidelberg pH capsule (HC) system. The integrity of the HC-delivery system tether was verified by fluoroscopy. RESULTS: The intra-individual variation in gastric emptying (GE) of the delivery system was large. There were also large inter-individual differences in the disintegration and absorption properties of the various formulations. However, the peak plasma concentrations of sCT were always observed when the intestinal pH declined. The average baseline intestinal pH was 6.1 +/- 0.2 (mean +/- SEM, n = 12). The intestinal pH reduction was 2.6 +/- 0.4 (mean +/- SEM, n = 12, ranged from 0.5 to 4.0 units from baseline). There was a good correlation between the time to reach the trough intestinal pH (t(pH,min)) and time to reach the peak plasma concentration (tconc,max)) of sCT (t(conc,max) = 0.95 x t(pH,min) + 14.1, n = 11, r2 = 0.91). Plasma Cmax and area under the curve (AUC) increased with increasing amounts of CA in the formulations. CONCLUSIONS: The results of these studies demonstrate that the oral absorption properties of a model peptide drug, sCT, can be modulated by changing intestinal pH. sCT is a substrate for the pancreatic serine protease trypsin which has maximal activity at pH 5 to 6. Reducing intestinal pH presumably stabilizes sCT in the GI tract enabling greater absorption of the intact peptide.

Absorption↗

PubMed1994

Nasal absorption in the rat. III. Effect of lysophospholipids on insulin absorption and nasal histology.

The intranasal absorption enhancing and histological effects of a range of lysophospholipids has been investigated in the rat. Blood glucose levels fell rapidly following the administration of insulin (8 IU/kg) in combination with lysophosphatidylcholines (LPC; 0.625% w/v) which had ten or more carbon groups in their fatty acid chain. The effect of the LPC-caproyl (C6) was comparable to that of an unenhanced insulin formulation; the enhancing effect of LPC-decanoyl (C10) was similar to that of an LPC-palmitoyl/stearoyl (C16/C18) for similar concentrations. The effect of LPC-decanoyl was reduced with concentration but was still significant at 0.2% w/v (5mM). Lysophosphatidylglycerol (LPG) had a marked insulin absorption enhancing effect even at 0.0625% w/v. The histological effects of LPC-caproyl were similar to those of an unenhanced insulin formulation, while co-administration of LPC-decanoyl resulted in evidence of epithelial interaction. LPG (0.5% w/v) resulted in similar histological changes as LPC (0.625% w/v) (1), but at 0.0625% w/v no significant changes in epithelial integrity were observed. The length of the fatty acid residue of lysophospholipids was identified as an important factor for intranasal absorption enhancing activity. The nature of the polar head group may also have an influence. Increased insulin absorption was not necessarily accompanied by severe disruption of the nasal epithelium. Careful selection of lysophospholipid type and concentration may enable therapeutic drug levels to be achieved via the nasal route without prohibitive toxic effects.

Absorption↗

PubMed1976

Food iron absorption in human subjects. IV. The effects of calcium and phosphate salts on the absorption of nonheme iron.

The influence of physiological levels of calcium and phosphorus on the absorption of nonheme iron from a semisynthetic meal was evaluated. Each of the 34 participating subjects received two to four test meals. In three studies where both calcium and phosphate were added, absorption of nonheme iron was reduced to 27 to 47% of that absorbed when no salts were added. However, with the single addition of either calcium or phosphate to the test meals no significantly inhibiting effect was observed. As the absorption of nonheme iron was significantly reduced only with the combined addition of calcium and phosphate, it is suggested that a calcium-phosphate-iron complex forms which inhibits iron absorption.

Absorption↗

PubMed2003

Reference range for gastrointestinal oxalate absorption measured with a standardized [13C2]oxalate absorption test.

PURPOSE: Hyperoxaluria is a prominent risk factor for calcium oxalate urinary stones. Oxalate in urine is synthesized in the body or absorbed from food in the gastrointestinal tract. The amount of oxalate absorbed by patients with calcium oxalate stones may vary from a few percent to 50% of the dietary intake. Reference values for oxalate absorption measured under a standardized diet have never been attained in sufficient numbers from healthy individuals. Therefore, to our knowledge we collected for the first time the values required to interpret test results in patients with recurrent urinary stones. MATERIALS AND METHODS: A total of 120 healthy volunteers, including 60 females and 60 males, received an identical standard diet on 2 consecutive days. On the morning of day 2 a capsule containing 0.37 mmol. sodium [13C2]oxalate (not radioactive) was ingested with water. Urinary oxalate was measured by gas chromatography-mass spectrometry. Absorption at a fixed 800 mg. daily Ca input is expressed as a percent of the labeled oxalate dose. RESULTS: For the standardized [13C2]oxalate absorption test the reference range in 95% of the 120 volunteers was 2.2% to 18.5% (mean +/- SD 7.9% +/- 4.0%). The repeatability of the standardized test was determined in 26 of the 120 volunteers by repeating the test twice. The mean intra-individual SD was 3.39% +/- 1.68%. CONCLUSIONS: We assessed reference values of intestinal oxalate absorption using a standardized diet. Interindividual and intra-individual variance was high.

Absorption↗

PubMed1976

Absorption from different types of iron tablets - correlation between serum iron increase in total absorption of iron.

The absorption of iron from three different iron tablets - rapidly-disintegrating ferrous sulphate and ferrous carbonate tablets and slow-release ferrous sulphate tablets - was studied in healthy subjects with a serum iron technique and by whole-body counter measurements. A solution of ferrous sulphate was used as a reference. There were no differences in the absorption from the ferrous sulphate preparations, but the ferrous carbonate tablets were less well absorbed. Good correlation was found between the maximal serum iron response and the total absorption of iron and it was concluded that serum iron studies may be used for semiquantitative measurements of iron absorption in comparative studies on different iron preparations.

Adult↗

PubMed2005

Estimating human drug oral absorption kinetics from Caco-2 permeability using an absorption-disposition model: model development and evaluation and derivation of analytical solutions for k(a) and F(a).

Intestinal transcellular permeability (P(m)), measured across cell lines such as Caco-2 cells in vitro, is often used for assessing oral drug absorption potential in humans. However, the quantitative link between in vitro permeability and apparent in vivo absorption kinetics, based on drug appearance in plasma, is poorly understood. In the current study, a novel absorption-disposition kinetic model that links traditional pharmacokinetic and mass transfer models was developed. Analytical solutions of k(a) and F(a) were deduced, and using Caco-2 permeability, F(a) in humans was predicted for 51 structurally diverse compounds. Predicted F(a) values were similar to and correlated highly with their corresponding experimental values with an average error of 1.88 +/- 1.06% (-17 to 22%) and r2 = 0.934. Simulated concentration profiles for 17 of 18 drugs corresponded to observed plasma concentration profiles in healthy volunteers. The equilibrium solution for k(a) (k(a,eq)) was found to be a key determinant of F(a), whereas under sink conditions, k(a) is likely to be a determinant of plasma concentration kinetics. The current version of the model offers a quantitative approach for predicting human oral absorption kinetics from in vitro permeability. It also establishes, for the first time, a quantitative link between P(m) and k(a) and between k(a,eq) and F(a). This will facilitate better in vitro or in situ-in vivo correlations since it establishes a basis for incorporating permeability coefficients from the various experimental formats based on drug loss or appearance that are commonly used in the laboratory for permeability determination.

Algorithms↗

PubMed1988

Absorption of bile acids in dog as determined by portal blood sampling: evidence for colonic absorption of bile acid conjugates.

The intestinal phase of enterohepatic circulation, such as site and state of bile acid absorption, along the length of the intestinal tract has been speculated but not directly quantitated. In order to gain insight into the actual state of intestinal absorption of bile acid, the bile acid composition of portal blood from various segments of the intestinal tract was studied in dogs after loading endogenous bile acid by injection of caerulein. Total and unconjugated bile acids were determined with and without enzymatic hydrolysis, respectively. The amount of conjugated bile acids was calculated by subtracting unconjugated from total bile acids. Quantitation of cholic, chenodeoxycholic, deoxycholic and lithocholic acids and their conjugates was carried out by gas chromatography/mass spectrometry/selected ion monitoring with deuterated bile acids as internal standards. The major site of absorption of taurine-conjugated bile acid, a major conjugate form in the dog, was the distal small intestine. In addition, a considerable amount of cholic acid was found to be absorbed from the distal large intestine, the majority of which was still in the conjugated form. The pronounced absorption of the unconjugated secondary bile acid from the large intestine suggests the very active formation of the secondary bile acid in situ.

Animals↗

PubMed1988

Bicarbonate absorption stimulates active calcium absorption in the rat proximal tubule.

To evaluate the effect of luminal bicarbonate on calcium reabsorption, rat proximal tubules were perfused in vivo. Perfusion solution contained mannitol to reduce water flux to zero. Total Ca concentration was measured by atomic absorption spectrometry, Ca ion concentration in the tubule lumen (CaL2+) and the peritubular capillary (CaP2+), and luminal pH (pHL) with ion-selective microelectrodes and transepithelial voltage (VTE) with conventional microelectrodes. When tubules were perfused with buffer-free Cl-containing solution, net Ca absorption (JCa) averaged 3.33 pmol/min. Even though VTE was 1.64 mV lumen-positive, CaL2+, 1.05 mM, did not fall below the concentration in the capillary blood, 1.07 mM. When 27 mM of Cl was replaced with HCO3, there was luminal fluid acidification. Despite a decrease in VTE and CaL2+, JCa increased to 7.13 pmol/min, indicating that the enhanced JCa could not be accounted for by the reduced electrochemical gradient, delta CCa. When acetazolamide or an analogue of amiloride was added to the HCO3 solution, JCa was not different from the buffer-free solution, suggesting that HCO3-stimulated JCa may be linked to acidification. To further test this hypothesis, we used 27 mM Hepes as the luminal buffer. With Hepes there was luminal fluid acidification and JCa was not different from the buffer-free solution but delta CCa was significantly reduced, indicating enhanced active calcium transport. We conclude from the results of the present study that HCO3 stimulates active Ca absorption, a process that may be linked to acidification-mediated HCO3 absorption.

Absorption↗

PubMed2004

Studies on intestinal absorption of sulpiride (3): intestinal absorption of sulpiride in rats.

The aim of this study was to investigate whether the concomitant administration of the substrates or inhibitors of PEPT1, OCTN1, OCTN2, and P-glycoprotein affects the intestinal absorption of sulpiride in rats. The absorption of sulpiride from rat intestine was decreased by the substrates or inhibitors of PEPT1, OCTN1, and OCTN2. On the other hand, the absorption was increased by the substrates of P-glycoprotein. The effects of these concomitantly administered drugs on the pharmacokinetic behavior of sulpiride after oral administration in rats were investigated. Peak concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-8 h)) of sulpiride were decreased by the concomitant administration of the substrates or inhibitors of PEPT1, OCTN1, and OCTN2. However, the same parameters were significantly increased by the concomitant administration of the substrates of P-glycoprotein. The present results suggest the possibility of drug-drug interaction during the absorption process in the small intestine due to the coadministration of sulpiride and these agents. These findings provide important information for preventing adverse effects and for ensuring the effectiveness of sulpiride and concomitantly administered drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1988

Studies on intestinal lymphatic absorption of drugs. II. Glyceride prodrugs for improving lymphatic absorption of naproxen and nicotinic acid.

A series of alpha- and beta-monoglycerides and triglyceride derivatives of naproxen or nicotinic acid were synthesized and investigated in order to elucidate the molecular form of the derivative with properties that enhanced lymphatic absorption. The lymphatic absorption rate was increased by adjusting the length of an n-alkyl chain introduced between the alpha- or beta-position of glycerol and the drug residue. The alpha- and beta-monoglyceride derivatives (containing an n-alkyl chain) were approximately equal in lymphatic absorption rates, but differed markedly in the concentration of the di- and triglyceride analogues in the lymph lipids. The lymphatic absorption of triglyceride derivatives, drugs combined directly with beta-position of glycerol, was low in comparison with the monoglyceride derivatives. Compared with nicotinic acid, the alpha-monoglyceride derivative (n-alkyl chain length, Cn = 20) of nicotinic acid provided a higher AUC0-8 h value of free nicotinic acid and maintained a lower level of free fatty acids in blood.

Animals↗

PubMed1982

Intestinal absorption of several beta-lactam antibiotics. III. Competitive inhibition behavior among zwitterionic beta-lactam antibiotics in the rat intestinal absorption.

Competitive inhibitory behavior among zwitterionic beta-lactam antibiotics in the rat intestinal absorption process was examined. Intestinal absorption of cephradine and cephalexin was significantly inhibited by cyclacillin. The mutual inhibition between these amino-cephalosporins was also observed. On the other hand, in the pretreatment experiments with cyclacillin, it was found that absorption of cephradine was significantly inhibited, but the inhibitory effect of cyclacillin was not observed for cephalexin. These results showed that cephradine had a common carrier-mediated transport mechanism with cyclacillin which is not present in the absorption process of cephalexin. It was postulated that the mutual inhibition between cephradine and cephalexin is based on the competitive inhibition in the accumulation or uptake by the intestinal mucosa.

Animals↗

PubMed1984

Drug absorption from the gastrointestinal tract and immunity: the mechanism of the decreased absorption of salicylic acid during systemic anaphylaxis. II.

Rats were intraperitoneally immunized with ovalbumin (egg albumin) with incomplete Freund's adjuvant, and the effect of intravenous challenge with ovalbumin on the intestinal blood flow was measured by means of hydrogen clearance method. The intestinal blood flow was significantly reduced by the antigen challenge in ovalbumin-immunized rats compared to the non-immunized rats. However, no significant change was observed on the intestinal blood flow in rats without challenge of the antigen. Moreover, the blood flow reduction was not found in ovalbumin-immunized rats challenged with bovine gamma-globulin. The effect was maintained for at least 16 weeks after the third immunization, but the reduced blood flow was gradually restored to the control level. The decrease in both blood flow and absorption of salicylic acid was recovered by nearly 70% of the control level when high dose of theophylline or caffeine was administered intravenously. In the case of gastric absorption during systemic anaphylaxis, similar results were also obtained by means of in situ loop technique. The decreased absorption of salicylic acid from the rat stomach also correlate with the reduced gastric blood flow. These findings suggest that the decreased absorption of salicylic acid from the gastrointestinal tract might be affected by the reduced blood flow during systemic anaphylaxis.

Anaphylaxis↗

PubMed1992

Contribution of interstitial diffusion in drug absorption from perfused rabbit muscle: effect of hyaluronidase on absorption.

[3H]Water and [14C]inulin were injected into perfused rabbit muscle with or without hyaluronidase (300 units/ml) and their absorption into venous effluent from muscle was determined. Hyaluronidase accelerated the absorption of both compounds but the enhancement of [14C]inulin was much larger than that for [3H]water. The pharmacokinetic analysis of venous appearance curves based on a physiological diffusion model elucidated that interstitial diffusion of [14C]inulin was remarkably increased by hyaluronidase treatment, suggesting the existence of steric hindrance for it by the polysaccharide network under normal conditions. Enhancement of [3H]water diffusion was also detected although enhancement ratio was about one-half of that of [14C]inulin. Mean time necessary for each process was calculated using the statistical moment concepts. The results suggested predominant contribution of the interstitial diffusion process and secondary and little contribution of local perfusion flow and permeation process across the capillary wall, respectively, in total absorption of [14C]inulin. Effect of hyaluronidase on transcapillary movement of [14C]inulin was studied using an in vitro diffusion experiment with cultured endothelial cell monolayer and no enhancing effect was shown on [14C]inulin transport across the cell monolayer. The contribution of the local perfusion flow, on the other hand, was shown to be almost equivalent to that of the diffusion process in the total absorption of [3H]water.

Absorption↗

PubMed2003

A modified two-portion absorption model to describe double-peak absorption profiles of ranitidine.

BACKGROUND: The pharmacokinetics of oral drugs exhibiting double peaks cannot be adequately described by using conventional compartmental models. OBJECTIVE: To propose and evaluate a modified two-portion absorption model based on physiological and biopharmaceutical considerations to describe the double-peak concentration-time curve of ranitidine. MODEL DESIGN: The proposed model assumes that oral ranitidine is absorbed sequentially in two portions due to delayed gastric emptying, and thus includes a gut compartment in addition to the central and peripheral compartments. METHODS: Validation of the model was performed with respect to structural identifiability, parameter estimability and model applicability. Using initial estimates of parameters obtained from previous intravenous data, the model was used to fit oral ranitidine data from six subjects who manifested clear double-peak concentration-time profiles as well as from six subjects who showed irregular but apparent single-peak concentration-time curves. RESULTS: Based on goodness-of-fit criteria, the model fitted well for both double-peak and single-peak concentration-time curves of ranitidine (for the two groups: weighted residual sum of squares, 0.044 +/- 0.027 and 0.054 +/- 0.036; correlation between observed and model predicted concentrations, 0.995 +/- 0.003 and 0.995 +/- 0.005). Simulation studies with concentrations generated with 10% normally distributed random error showed that all model fitted parameters had good accuracy and reasonable precision. The mean percentage bias ranged from -7.0 to 28.6%, and the coefficient of variance was within 30% for the majority of parameters compared with the theoretical values. CONCLUSION: The modified two-portion absorption model may afford a useful approach to characterise the absorption phase and estimate pharmacokinetic parameters for drugs with two absorption peaks.

Adult↗

PubMed1975

Thiamine absorption in the rat. ii. intestinal alkaline phosphatase activity and thiamine absorption from rat small intestine in-vitro and in-vivo.

The correlations between intestinal alkaline phosphatase (IAP) activity and thiamine absorption and glucose absorption were studied in the rat. An everted sac in-vitro technique was used in adult rats whereas in-vitro experiments were performed in young rats 10 days old. All incubation experiments were done with 14-C-labeled thiamine. The patterns of IAP activity along the small intestines differed greatly between young and adult rats but were closely paralleled by the distribution of active thiamine transport in adult rats and thiamine absorption in young rats, respectively. When IAP was specifically inhibited in adult rats by L-phenylalanine active thiamine transport in-vitro was abolished. No correlation was found between IAP activity and active transport or glucose in-vitro, nor did inhibition of the enzyme in any way affect glucose transport capacity. It is suggested that the enzyme intestinal alkalinephosphatase is involved in the process of active thiamine absorption.

Age Factors↗

PubMed1988

Absorption of 'non-absorbable' markers and an improved method for determining cholesterol absorption rates.

The determination of uptake rates for lipids across absorptive epithelia, using radiolabelled compounds has normally used non-absorbable volume markers to correct gross tissue counts for contamination by adherent mucosal fluid. There is evidence however to indicate that the macromolecules traditionally used as non-absorbable markers are in fact absorbed. This may result in an overestimate of the apparent adherent mucosal fluid with consequent errors in the calculation of lipid uptake. An in-vitro method was used to assess cholesterol absorption by human gallbladder from artificial bile, containing 3H-dextran 70,000 as a 'non-absorbable' volume marker. Both cholesterol and dextran were transported through the mucosa and appeared on the serosal side of the gallbladder. Confirmation of dextran absorption was obtained by electron microscopic examination of the gallbladder epithelium. By using the serosal appearance of dextran as a guide to the amount of absorbed (intracellular) dextran in the tissue samples, we have derived a formula to calculate tissue dextran absorption and, from the revised adherent mucosal volume, have consequently obtained more realistic estimates of tissue lipid uptake. In this study, comparison made between the previous estimate of lipid uptake compared to this new calculation, showed that the previous technique significantly underestimated true lipid uptake.

Absorption↗

PubMed1985

Gastrointestinal aluminium absorption: is it modulated by the iron-absorptive mechanism?

Gastrointestinal aluminium (A1) absorption has been proved but its mechanism is still unknown. This study investigates the pattern of A1 absorption in patients with different degrees of iron stores. We studied 29 haemodialysis patients forming three groups according to their serum ferritin values. Over seven days all patients received the same dose of aluminium hydroxide after which patients with 'low-normal' and normal serum ferritin increased their serum A1 proportionally with the increased aluminium hydroxide intake. By contrast patients with high serum ferritin did not show any change in their serum A1 values. Our results therefore suggest that a 'common pathway' of metal absorption could be implicated in A1 absorption. Serum ferritin might be a valuable predictor of different behaviour.

Adult↗

PubMedDate not supplied

Absorption of amino acids in different parts of the small intestine in growing pigs. IV. Effect of sugars on absorption of amino acids and water.

The study was performed on pigs weighing 50-75 kg with temporarily isolated loops of the small intestine. The isolated segments were perfused with solutions containing casein hydrolysates and different concentrations of sugars (up to 50 g/l). The effect of the sugars depended on their type and amount, and on the type of the hydrolysate; addition of 10 g/l sugar to the enzymic hydrolysate of casein which was only partly hydrolysed did not affect absorption of the latter. The absorption of most amino acids was depressed in the presence of 20 g/l lactose or sucrose or of 20-50 g/l glucose, the effect of lactose being least evident. Sugars and amino acids stimulated the net absorption of water only from isotonic or slightly hypertonic solutions: addition of 50 g/l glucose significantly depressed the net absorption of water.

Amino Acids↗