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At least 217 records · Page 12Linked to original sources
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↗
PubMedDate not supplied

Absorption of amino acids in different parts of the small intestine in growing pigs. I. Absorption of free amino acids and water.

The study was on pigs weighing 50-75 kg with temporarily isolated loops of the proximal, middle and terminal small intestine. Isolated segments were perfused with solutions of acid hydrolysate of casein containing 8, 12 or 16 g free amino acids per litre. The capacity to absorb water increased along the small intestine reaching about 5 1/m/24 h in the distal part. The absorption of nitrogen from all solutions was least in the proximal small intestine (up to 8 g/m/24 h); there were no significant difference in nitrogen absorption between the other parts. The rates of absorption of various amino acids, were different and depended on the concentration of amino acids in the intestine. On the whole, the rates of absorption of essential amino acids were: Arg, Met, Ile, Leu greater than lys greater than Thr, His. From among the non-essential amino acids Glu and Gly were absorbed to the lesser extent than the other ones.

Amino Acids↗
PubMed1993

Studies on the reliability of a novel absorption-lipophilicity approach to interpret the effects of the synthetic surfactants on drug and xenobiotic absorption.

Some theoretical principles of the absorption/lipophilicity approach, which attempts to explain the effects of the synthetic surfactants on xenobiotic and drug intestinal absorption, are reviewed and experimentally checked by examining the correlations obtained between "in situ" absorption constants, ka, found in rat colon, and "in vitro" lipophilicity indexes, K', for two compound series (secondary aliphatic amines and phenylalkylamines) in the absence and in the presence of the nonionic surfactant Polysorbate 80, in the intestinal perfusion fluid. Evidence is given for the following actions of the synthetic surfactant: at its critical micelle concentration (CMC), it increases the polarity of the absorbing membrane and, at the same time, it disrupts the aqueous stagnant diffusion layer adjacent to the mucosal barrier. When a supramicellar concentration (SMC) is used, the above actions are almost totally masked by the micellar solubilization of the tested amines, which decreases their absorption constants relative to those found at CMC, as markedly as solute lipophilicity increases. As a consequence of these actions, the correlations between ka and K', which are clearly hyperbolic in free solution, become potential in the presence of the surfactant at its CMC, whereas at SMC a bilinear correlation is obtained. Absorption via lipophilic ionized species seems to take place for both compound series. Mathematical and physicochemical interpretations of this behaviour are outlined, and biopharmaceutical implications of these phenomena are discussed.

Amines↗
PubMed1997

Nonlinear intestinal absorption of 5-hydroxytryptamine receptor antagonist caused by absorptive and secretory transporters.

The mechanism of the nonlinear concentration dependence of intestinal absorption of the 5-hydroxytryptamine receptor antagonist azasetron was studied by use of rat in situ intestinal perfusion, as well as an in vitro Ussing-type chamber method mounted with rat intestinal tissue and cultured monolayers of human adenocarcinoma Caco-2 cells. The intestinal absorption rate constant of azasetron evaluated by the Doluisio method increased significantly with increasing concentration of azasetron up to 10 mM in a nonlinear fashion and tended to decrease at higher concentrations. Mucosal-to-serosal directed permeation of [14C]azasetron across rat ileal sheets evaluated by the in vitro Ussing-type chamber method also increased in a nonlinear fashion in a low concentration range, followed by a decrease as the concentration was further increased, whereas serosal-to-mucosal directed permeation decreased in a concentration-dependent manner. Vectorial transport of [14C]azasetron across a Caco-2 cell monolayer was observed, with higher transport in the basolateral-to-apical direction at a trace concentration of azasetron. When the initial uptake rate of azasetron by Caco-2 cells was measured, it was saturable with an apparent half-saturation concentration of 15 mM and was reduced in the presence of several cationic compounds. These observations suggest that azasetron is taken up by a carrier-mediated transport mechanism across the intestinal epithelial cells. When the steady-state uptake of [14C]azasetron was measured, it was increased in the presence of unlabeled azasetron and ondansetron. In addition, the steady-state uptake was enhanced in the presence of a P-glycoprotein inhibitor, cyclosporin A, and by ATP-depletion of the cells, although these treatments had no effect on the initial uptake of [14C]azasetron. Furthermore, the multidrug-resistant cancer cell line K562/ADM that overexpresses P-glycoprotein accumulated azasetron less extensively than did the parental drug-sensitive K562 cells. These results strongly suggest that azasetron is secreted into the intestinal lumen predominantly by P-glycoprotein. We conclude that intestinal transport of azasetron involves specialized transporters in both the absorptive and secretory directions, and the complex nonlinear intestinal absorption characteristics can be ascribed to the participation of multiple transport mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Ligation of the iron in the heme-heme oxygenase complex: X-ray absorption, electronic absorption and magnetic circular dichroism studies.

Heme oxygenase (HO) catalyzes the first steps in the breakdown of heme to biliverdin and carbon monoxide. It is a membrane-bound protein that has been shown to exist in two isoforms, HO-1 and HO-2. Recently, a soluble, truncated form of rat HO-1 (rHO) lacking the 23 amino-acid membrane anchor has been expressed in E. coli. Extended X-ray absorption fine structure (EXAFS) data on ferric rHO and its fluoride derivative support assignment of the axial iron ligands as oxygen and/or nitrogen donors having distances similar to ferric myoglobin. The electronic absorption and magnetic circular dichroism (MCD) spectra of the ferric and ferrous protoheme complexes of rHO as well as various ligand adducts are very similar to the corresponding spectra of myoglobin. The present study is the first investigation of the heme-heme oxygenase complex with EXAFS and MCD spectroscopy and establishes that the proximal ligand to the heme in rHO is histidine. Furthermore, the close similarity between the electronic absorption and MCD spectra of ferric rHO and myoglobin over the pH range 6 to 10 is consistent with distal heme ligation of ferric rHO as a water molecule or hydroxide ion, depending on pH. Taken together and in conjunction with the results of earlier studies, EXAFS, electronic absorption, and MCD spectroscopy solidly establish that the ligands to the heme in rHO are identical to those in myoglobin, namely, histidine/H2O at low pH and histidine/OH at high pH.

Animals↗
PubMed1999

A compartmental absorption and transit model for estimating oral drug absorption.

This report describes a compartmental absorption and transit model to estimate the fraction of dose absorbed and the rate of drug absorption for passively transported drugs in immediate release products. The model considers simultaneous small intestinal transit flow and drug absorption. Both analytical and numerical methods were utilized to solve the model equations. It was found that the fraction of dose absorbed can be estimated by F(a) = 1-(1+0.54 P(eff))(-7), where P(eff) is the human effective permeability in cm/h. A good correlation was found between the fraction of dose absorbed and the effective permeability for ten drugs covering a wide range of absorption characteristics. The model was able to explain the oral plasma concentration profiles of atenolol.

Adsorption↗
PubMed1967

Selective inhibition of absorption and long distance transport in relation to the dual mechanisms of ion absorption in maize seedlings.

The influence of several uncouplers of oxidative phosphorylation and inhibitors of terminal electron transport was studied on absorption and long distance transport of both K and C1 at concentrations within each range of the dual isotherm typical of ion uptake by maize roots. At low concentrations in the range of system 1, the system considered to implement ion movement through the plasma membrane, root absorption and long distance transport are equally inhibited by a given inhibitor. In the high range of system 2, the system considered to mediate ion passage through the tonoplast, long distance transport is markedly less sensitive to inhibitors than is absorption. The observations are in accord with the hypothesis that only system 1 is involved in the uptake of ions from the external solution into the symplast, and hence into the xylem. At high concentrations, entrance into the symplasm is deemed to be largely by diffusion and therefore less inhibitor sensitive. With respect to absorption by the roots, the plasma membrane system is more inhibitor sensitive than is the tonoplast system. It is suggested that the difference in sensitivity is real, and not the consequence of an inequality of inhibitor concentration in the vicinity of the plasma membrane and tonoplast respectively.

Biological Transport↗
PubMed1977

The absorption of phenformin and its effects on glucose and water absorption in isolated perfused rat small intestine.

The effects of phenformin on glucose and water absorption from isolated perfused rat small intestine were studied. Luminal phenformin inhibited glocose and water absorption progressively as its concentration was increased from 0-1-1-0 mg.ml-1. At 0-5 mg phenformin ml-1, inhibition increased with time of exposure to phenformin up to 15 min and thereafter remained constant. Arterial infusion of phenformin (1-0 mg-ml-1) produced less inhibition of glucose and water absorption. The site of phenformin's action appeared to be intracellular. Phenformin absorption from a luminal perfusate (0-5 mg-ml-1) was measured. Although it was rapidly absorbed (22 microgram.cm intestine-1.h-1) from the lumen, less than 2 microgram.cm-1.h-1 appeared at the serosal surface of the intestine. In subsequent phenformin-free perfusion, only 25% of the absorbed phenformin was recovered in the luminal and serosal effluents.

Animals↗
PubMed2000

Absorption enhancement of a protein drug by nitric oxide donor: effect on nasal absorption of human granulocyte colony-stimulating factor.

The objective of this study was to evaluate the effect of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), on the nasal absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rabbits and to evaluate the irritation (cytotoxicity) potential of the NO donor on the mucosal membrane using a cultured cell system (strain KB, human epidermoid carcinoma of the floor of the mouth). Significantly higher serum G-CSF concentration and increased total leukocyte count in the peripheral blood were observed after coadministration of rhG-CSF (100 microg/kg) with SNAP at various doses (0.3-3.3 mg/kg). The serum G-CSF concentration and the increased total leukocyte count were markedly decreased by the presence of the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazole-1-oxyl 3-oxide sodium salt (carboxy-PTIO), in combination with rhG-CSF and SNAP. However, no significant inhibitory effect of glutathione (peroxynitrite scavenger) on the absorption-enhancing effect of SNAP was observed. These results suggest that carboxy-PTIO inhibits the absorption-enhancing effect of NO released from SNAP. We found that SNAP has a very low potential for cytotoxicity, as evaluated by the cell detachment assay, release of lactate dehydrogenase (LDH) from cultured cells and morphological observations of nasal tissue of rabbits. It is concluded that a NO donor such as SNAP is a promising absorption enhancer for nasal protein-drug delivery.

Administration, Intranasal↗
PubMed1992

Characterization of the oral absorption of several aminopenicillins: determination of intrinsic membrane absorption parameters in the rat intestine in situ.

The absorption mechanism of several penicillins was characterized using in situ single-pass intestinal perfusion in the rat. The intrinsic membrane parameters were determined using a modified boundary layer model (fitted value +/- S.E.): Jmax* = 11.78 +/- 1.88 mM, Km = 15.80 +/- 2.92 mM, Pm* = 0, Pc* = 0.75 +/- 0.04 for ampicillin; Jmax* = 0.044 +/- 0.018 mM, Km = 0.058 +/- 0.026 mM, Pm* = 0.558 +/- 0.051, Pc* = 0.757 +/- 0.088 for amoxicillin; and Jmax* = 16.30 +/- 3.40 mM, Km = 14.00 +/- 3.30 mM, Pm* = 0, Pc* = 1.14 +/- 0.05 for cyclacillin. All of the aminopenicillins studied demonstrated saturable absorption kinetics as indicated by their concentration-dependent wall permeabilities. Inhibition studies were performed to confirm the existence of a nonpassive absorption mechanism. The intrinsic wall permeability (Pw*) of 0.01 mM ampicillin was significantly lowered by 1 mM amoxicillin and the Pw* of 0.01 mM amoxicillin was reduced by 2 mM cephradine consistent with competitive inhibition.

Absorption↗