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PubMed1994

Variable gastric emptying and discontinuities in drug absorption profiles: dependence of rates and extent of cimetidine absorption on motility phase and pH.

The influence of various fasting-state gastrointestinal parameters on variability in absorption of cimetidine was studied using simulation and cimetidine administration as a duodenal infusion and as an oral tablet in fistulated mongrel dogs. In the simulation studies, the frequency of double-peak occurrence in plasma profiles was estimated employing average gastric emptying rates as well as interdigestive-migrating-motor-complex (IMMC) phase lengths that were systematically altered. Emptying rates and phase lengths were modeled as periodic step functions. Simulations indicated that double peaks occur when gastric emptying of the drug begins in early phase I or late phase II/III, which represent the periods of very low, medium, and high gastrointestinal motility, respectively. The incidence is increased for longer phase-I duration and higher elimination rate constants. For a compound with a 2 h elimination or disposition half-life, two concentration maxima (double peaks) were found in 12% of the simulated concentration-time profiles. The double peak frequency in simulated curves was considerably higher for t1/2 < 30 min. When cimetidine was administered to dogs as a duodenal infusion in the active and quiescent motility phases, discontinuous profiles were observed, although the variability of the various parameters was reduced when compared. Pharmacokinetic models were set up that were characterized by multi-segmental input (one- to 3-lag-time models were used) for the profiles resulting from oral and duodenal administration. The lag time for the first process characterized the onset of absorption. A significant difference between phases was detected for infusions at pH 8, where the initial lag time was longer in the quiescent phase. The mean input time (MIT) was calculated as the integral input parameter. There was a tendency for the MIT to be higher for pH 6 infusions than for pH 4 and pH 8. Bioavailability analysis indicated that cimetidine was more rapidly and completely absorbed at pH 8 than at pH 6. Bioavailability was also slightly higher at pH 4 than at pH 6. We concluded that gastric emptying increased the variability of the cimetidine concentration-against-time profiles and that it plays a role with respect to double-peak occurrence, although it is only one of several causative factors.

Administration, Oral↗
PubMed2004

Assessment system for dioxin absorption in the small intestine and prevention of its absorption by food factors.

It has been reported that 90% of the amount of dioxin in the whole body is absorbed orally with food. However, a concise and simple system to assess dioxin absorption in the small intestine has not yet been established. The present study reports a new in vitro assessment system for this purpose. A stable dioxin-responsive cell line was established by introducing a plasmid that incorporates a xenobiotic-responsive element upstream of the luciferase gene into human hepatic HepG2 genomic DNA. Dioxin was added to the apical side of differentiated human intestinal epithelial Caco-2 cell monolayers that had been cultured on a semipermeable membrane, and the basal medium was recovered after an appropriate incubation time. To the recovered medium was added dioxin-responsive HepG2, and a luciferase assay was performed. The established stable cell line clearly showed dose-and time-dependent response to dioxin. When a food factor such as chlorophyll, which has been reported to increase dioxin excretion in in vivo studies, was added with dioxin, a significant decrease in dioxin permeability to the Caco-2 monolayer was observed. This assessment system would be useful to search for those food factors that could prevent dioxin absorption in the small intestine.

Carcinoma, Hepatocellular↗
PubMed1977

Effect of surfactants on absorption through membranes V: Concentration-dependent effect of a bile salt (sodium deoxycholate) on absorption of a poorly absorbable drug, phenolsulfonphthalein, in humans.

The effect of administration of 600-and 300-mg doses of sodium deoxycholate 1 hr before phenolsulfonphthalein solution is reported. The 600-mg dose caused a decrease in drug bioavailability as measured by the total amount excreted in 24 hr. The 300-mg dose cause and increase in the initial phenolsulfonphthalein absorption rate, suggesting a direct action of the bile salt on membrane permeability. The decrease in absorption upon administration of 600 mg was attributed to micellar entrapment of the drug molecule.

Adult↗
PubMed1981

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics I: Comparative absorption and evidence for saturable transport of amino-beta-lactam antibiotics by in situ rat small intestine.

The disappearance of various beta-lactam antibiotics from in situ rat small intestinal loops was studied at pH 7.4. For monobasic penicillins, despite the wide variety of apparent partition coefficients in isobutyl alcohol-water, the disappearance from the jejunal loops was almost 30% (+/- 5% SD). On the other hand, the disappearance of amphoteric derivatives of penicillins and cephalosporins having very low lipid solubility varied widely between 12 and 80%. The peak blood levels after intraduodenal administration to the rats correlated well with the extent of disappearance of amphoteric penicillins from the intestinal loops. Absorption studies utilizing in situ intestinal loops were performed at variable dose ranges to yield a clear dose-dependent disappearance. It is suggested that certain carrier-mediated transport systems underlie the absorption mechanism of amphoteric beta-lactam antibiotics.

Animals↗
PubMed1981

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics II: Michaelis-Menten kinetics of cyclacillin absorption and its pharmacokinetic analysis in rats.

The absorption of cyclacillin at pH 7.0 by the rat small intestine was investigated using in situ perfusion. At the lowest dose of 95 microgram/ml, the antibiotic disappearance was rapid and followed first-order kinetics, with the disappearance being 85% at 100 min. At the intermediate concentrations of 770 and 1200 microgram/ml, the disappearance after 100 min was 69 and 54%, respectively, and semilogarithmic plots clearly showed convex curvatures. At the highest concentration of 30 mg/ml, cyclacillin disappeared slowly from the perfusate, in an apparent first-order fashion. The disappearance was 26% after 100 min of perfusion and was similar in extent at 5.2 mg/ml. This concentration-time profile was satisfactorily fitted to the simultaneous Michaelis-Menten and first-order kinetic equations. The area under the blood concentration versus time curve (AUC) after a single intraduodenal dose of cyclacillin was almost consistent with the AUC after the equivalent intravenous dose (10 mg/kg). Additional evidence from a pharmacokinetic analysis of steady-state blood concentrations after constant infusion of cyclacillin through the portal vein and the small intestinal lumen indicated that cyclacillin absorption by the rat intestinal tissue at relatively low concentrations (less than 1 mg/ml) followed solely Michaelis-Menten kinetics. Cyclacillin may be transported by certain types of carrier-mediated mechanisms.

Animals↗
PubMed1984

The effects of salicylate on the rectal absorption of phenylalanine and some peptides, and the effects of these peptides on the rectal absorption of cefoxitin and cefmetazole.

The disappearance of phenylalanine and phenylalanylglycine from a perfusate circulated across rat rectal tissue was enhanced significantly in the presence of salicylate or 5-methoxysalicylate at pH 4.5, 7.4, and 8.5. The disappearance of di-, tri-, and tetraphenylalanine from a perfusate at pH 7.4, although facilitated by the presence of salicylate and 5-methoxysalicylate, was also fairly substantial when no adjuvant was present. These peptide analogues of phenylalanine also enhanced the rectal absorption of cefoxitin and cefmetazole, two highly water soluble antibiotics. Phenylalanine and phenylalanylglycine, both poorly absorbed across the rectal membrane when administered alone, did not enhance the rectal absorption of either antibiotic.

Animals↗
PubMed1982

Synthetic human gastrin I and gastrin-like pentapeptide in studies of intestinal absorption in man. Role of gastrin in human intestinal absorption.

The effects of synthetic human gastric I (SHG I) and gastrin-like pentapeptide (PG) on jejunal water, electrolyte, and glucose absorption were studied in 11 normal subjects. The i.v. administration of graded doses of SHG I increased plasma gastrin levels similar to those after food intake and in the Zollinger-Ellison syndrome. SHG I and PG caused no significant changes in the net movement of water and solute. The findings indicate that gastrin has no direct effect on intestinal absorption in normal man, and does not account for the mechanism of diarrhea in the Zollinger-Ellison syndrome.

Adult↗
PubMed1997

Permethrin absorption not detected in single-pass perfused rabbit ear, and absorption with oxidation of 3-phenoxybenzyl alcohol.

Isolated rabbit ears were single-pass perfused with a protein-free medium. Permethrin (0.05-23.5%, w/w) was applied in four distinct ointments. Permethrin, 3-phenoxybenzyl alcohol, 3-phenoxybenzaldehyde, and 3-phenoxybenzoic acid were analysed by HPLC. Permethrin was not detected in the effluent. The permeation coefficient, calculated from the detection limit was < 7.3 x 10(-12) (cm/sec). The appearance rate of the 3-phenoxybenzyl moieties in the effluent agreed with the absorption of the corresponding impurities in the various ointments. In supernatant of homogenised skin, the hydrolysis rate of permethrin was linear; about 4 pmol/min per cm2 at 10 microM substrate concentration. The proportion of 3-phenoxybenzoic acid, a further metabolite of 3-phenoxybenzyl alcohol increased when an oxidizing co-factor system was added. The appearance rate in the effusate of 3-phenoxybenzyl alcohol following the lipophobic ointment was five times faster than from isopropyl myristate. The formation rate of 3-phenoxybenzoic acid followed saturation kinetics. Occupational systemic poisoning by dermal absorption of permethrin seems very unlikely since humans bear more epithelial cell layers than rabbits. These experiments do not contradict, however, possible paraesthesia during systemic poisoning after inhalation or ingestion of the pyrethroid-containing aerosols used in agriculture.

Animals↗
PubMed1977

Iron absorption in infants: high bioavailability of breast milk iron as indicated by the extrinsic tag method of iron absorption and by the concentration of serum ferritin.

Breast feeding is thought to result in a lower incidence of iron deficiency than does the use of unfortified cow milk forumalas, but there is scant documentation for this belief. The relationship of breast and cow milk feeding to absorption of iron and to iron status was investigated in a total of 45 term infants at about six months of age. Iron absorption was measured by total body counting. Laboratory assessment of iron status was based on the serum ferritin, hemoglobin, mean corpuscular volume, and transferrin saturation. The results indicated that infants fed breast milk during the entire first six to seven months of life attained greater iron stores than did those fed a cow milk formula. Breast-fed infants absorbed an average of 49% of a trace dose of extrinsic iron administered during a breast feeding in contrast to about 10% reported to be absorbed from cow milk under similar conditions. The data indicate that term infants who are breast fed may not require routine administration of supplemental iron.

Animals↗
PubMed1990

Solute absorption from the airways of the isolated rat lung. III. Absorption of several peptidase-resistant, synthetic polypeptides: poly-(2-hydroxyethyl)-aspartamides.

A series of samples of the synthetic polypeptide poly-alpha, beta-[N(2-hydroxyethyl)-DL-aspartamide] (PHEA), containing covalently bound fluorophore, ethylcarbonyl-6-aminofluorescein, and exhibiting different molecular weight distributions with weight average molecular weights ranging from approximately 4 to 43 kD, was prepared and characterized. Aqueous solutions of the polymers were administered to the airways of isolated perfused rat lung preparations, and transfer to the perfusate was measured. Polymers administered directly to the perfusate were not degraded during the experiment. Polymer transfer rates were dependent upon starting molecular weight distribution, larger molecules being absorbed more slowly. In the case of a polymer with a median molecular weight of 7.2 kD, the absorbed species appeared to be smaller molecules than those which were originally administered. This was not the case for a 3.98-kD polymer; absorbed material had a gel permeation chromatography elution volume equivalent to that of the administered material. Absorption for the 3.98-kD polymer was found to be dose dependent. Approximately 70% absorption of a 0.2-mg dose occurred in 100 min. Much larger polymers (up to 11.65 kD) were also absorbed at finite rates. Results are discussed in the context of macromolecular delivery to the systemic circulation via the lung.

Absorption↗
PubMed1994

Oral absorption of peptides: the effect of absorption site and enzyme inhibition on the systemic availability of metkephamid.

In this study the intestinal degradation and absorption of a synthetic pentapeptide, metkephamid, were investigated in the rat by determination of its wall permeabilities in the small and large intestine and the extent and mechanism of its intestinal degradation. The peptide was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane. The extent of metabolic inactivation depended on the intestinal segment investigated and decreased in the axial direction. No metabolism was found in the colon. The dimensionless wall permeabilities (Pw*), determined by single-pass perfusion, were also site dependent. Pw* was highest in the ileum [1.91 +/- 0.24, (SE); n = 4], followed by the jejunum (1.64 +/- 0.34; n = 4) and the colon (0.67 +/- 0.38; n = 4). Based on the permeability data alone and under the assumption of no presystemic metabolism, complete bioavailability would be predicted for metkephamid. However, following oral administration, the mean absolute bioavailability was only 0.22 +/- 0.065% (n = 3), indicating the overall dominance of degradation in the absorption process. Thus future strategies in oral peptide delivery should focus on increasing the stability of the peptide in the intestine by modifying the peptide structure and/or delivering the compound to an intestinal segment showing little or no enzymatic degradation.

Amino Acid Sequence↗
PubMed1994

Cyclodextrins as mucosal absorption promoters of insulin. II. Effects of beta-cyclodextrin derivatives on alpha-chymotryptic degradation and enteral absorption of insulin in rats.

The relative effectiveness of two beta-cyclodextrin derivatives, i.e., dimethyl-beta-cyclodextrin (DM beta CD) and hydroxypropyl-beta-cyclodextrin (HP beta CD), in enhancing enteral absorption of insulin was evaluated in the lower jejunal/upper ileal segments of the rat by means of an in situ closed loop method. The incorporation of 10% (w/v) DM beta CD to a 0.5 mg/ml porcine-zinc insulin solution dramatically increased insulin bioavailability from a negligible value (approximately 0.06%) to 5.63%, when administered enterally at a dose of 20 U/kg. However, addition of 10% (w/v) HP beta CD did not improve enteral insulin uptake significantly with a bioavailability of only 0.07%. Similarly, the pharmacodynamic relative efficacy values obtained after the enteral administration of 20 U/kg insulin, 20 U/kg insulin with 10% HP beta CD, and 20 U/kg insulin with 10% DM beta CD were 0.24%, 0.26%, and 1.75%, respectively. Biodegradation studies of 0.5 mg/ml insulin hexamers by 0.5 microM alpha-chymotrypsin revealed no inhibitory effect on the enzymatic activity by the two cyclodextrins. On the contrary, the apparent first-order rate constant increased significantly in the presence of 10% DM beta CD, suggesting insulin oligomer dissociation by DM beta CD. Histopathological examination of the rat intestine was performed to detect tissue damage following enteral administration of the beta-cyclodextrin derivatives. Light microscopic inspection indicated no observable tissue damage, thereby arguing direct membrane fluidization as the primary mechanism for enhanced insulin uptake. This study indicates the feasibility of using cyclodextrins as mucosal absorption promoters of proteins and peptide drugs.

Administration, Oral↗
PubMed1985

Food-induced changes in theophylline absorption from controlled-release formulations. Part I. Substantial increased and decreased absorption with Uniphyl tablets and Theo-Dur Sprinkle.

Food-induced changes in absorption from two controlled-release formulations of theophylline (Uniphyl tablets [Purdue Frederick Co.] and Theo-Dur Sprinkle [Key Pharmaceuticals, Inc.]) were studied in healthy male nonsmokers. Although the two forms exhibited a theophylline in vitro dissolution rate that was independent of changes in pH from 1 to 8, they showed substantial but opposite food-induced absorption changes. In a 12-subject, three-way, single-dose, randomized, crossover study the bioavailability of theophylline relative to immediate-release aminophylline tablets increased from 53% +/- 23% (means +/- SD) to 96% +/- 46% when Uniphyl (two 400 mg tablets) was taken under fasting and nonfasting (high fat content meal) conditions, respectively. On the other hand, in a separate six-subject, two-way, randomized, crossover study, food reduced the bioavailability of theophylline from Theo-Dur Sprinkle: Theophylline bioavailability in the nonfasting state was only 53% +/- 9% that in the fasting state.

Absorption↗
PubMed2004

Photophysical properties of a carbazolyl mesogen of 8PCzC as revealed by absorption, fluorescence, and transient absorption measurements.

Fluorescence spectra in three phases [crystalline, smectic A liquid crystal (SmA), and isotropic] of a mesogen including one carbazolyl (Cz) chromophore, 4'-n-octylphenyl carbazole-2-carboxylate (8PCzC), were measured at various temperatures and compared with fluorescence spectra in solvents with various dielectric constants. Further, for the first time, picosecond transient absorption spectroscopy was applied to elucidating photoinduced electron-transfer dynamics (charge separation, charge recombination, and hole transfer reactions) in the three phases of 8PCzC doped with a small amount of an electron acceptor. The fluorescence spectra showed clearly the presence of two crystalline phases, which was supported by DSC measurement. On the basis of a comparison of the fluorescence spectra and those in solution, the 8PCzC molecule in the first crystal structure was suggested to be in polar environment compared to that in the second one. The fluorescence yields of 8PCzC in both SmA and isotropic phases were remarkably small compared to that in crystalline one. This was ascribed to the formation of hydrogen bonds between 8PCzC molecules in both SmA and isotropic phases. As a first approximation, the picosecond transient absorption spectra in the three phases of 8PCzC doped with 2,4,7-trinitrofluorenone were analyzed by the simple model of one-dimensional hole migration. The rate constants obtained for the hole transfer from the cation state of Cz chromophore to neighboring Czs decreased in the order of SmA (approximately 10(9) s(-1)) > isotropic (approximately 10(8) s(-1)) > crystalline (approximately 10(7) s(-1)) phases, although these measurement temperatures were different.

Absorption↗
PubMed1999

Metabolism of pamaqueside, a cholesterol absorption inhibitor, in Long-Evans rat: effect of bile duct cannulation on absorption.

The metabolism of pamaqueside, a cholesterol absorption inhibitor, was studied in the bile duct cannulated and non-cannulated rat after an oral dose (100 mg/kg) and an i.v. dose (6 mg/kg) of [14C]pamaqueside. Faeces was the major route of excretion in all rat. Only 0.1% of the radioactivity was recovered in the urine of the non-cannulated rat. In contrast, approximately 17% of the total dose was recovered in the bile and urine in the bile duct cannulated rat. Following an i.v. dose, an almost equal percentage of radioactivity was excreted in the bile and urine of the bile duct cannulated rat. 3. The aglycone (M1) was the major metabolite in rat and was present in greater amounts in the faeces of the bile duct cannulated rat. The structural elucidation of metabolites in the bile and urine indicated that M1 was metabolized oxidatively via a novel ring opening, and the oxidative metabolites further underwent sulphate conjugation. The oxidative ring opening of pamaqueside (the cellobioside ring intact) was also observed following an i.v. dose to rat suggesting that oxidative ring opening was the major route of metabolism of saponins, at least in rat. The study demonstrated that the absorption and metabolism of pamaqueside was altered by surgical cannulation of rat.

Animals↗
PubMed1950

Radioiron absorption in anemic dogs; fluctuations in the mucosal block and evidence for a gradient of absorption in the gastrointestinal tract.

The control of iron absorption appears to reside in the mucosa of the gastrointestinal tract. The normal dog absorbs very little iron, but the anemic iron-depleted dog may absorb 10 to 20 times as much. This "mucosal block" of the normal dog probably is due largely to iron stores in the mucosa. "Mucosal block" can be effected in the anemic iron-depleted dog by feeding of iron salts, but the degree of "mucosal block" under these conditions never reaches the high degree of "mucosal block" in the normal dog. Rapid movement of iron through the mucosa may explain the short duration of "mucosal block" due to iron feeding in the anemic iron-depleted dogs (18 to 20 hours, Fig. 1). The colon absorbs very little iron under the conditions described. The stomach and duodenum seem to be most active in its absorption. This suggests the existence of a gradient in the capacity of the gastrointestinal tract to absorb iron.

Anemia↗