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PubMed1996

The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers.

An open-label, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy volunteers (between 20 and 44 years of age) to assess the effect of orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption and is being developed for weight control in obesity, on the absorption of vitamins A and E. Each participant received a single oral dose of 25,000 IU vitamin A followed 24 hours later by a single oral dose of 400 IU vitamin E on two separate occasions: during oral administration of 120 mg orlistat or placebo three times daily for 9 days. The two treatments were separated by a washout period of at least 2 weeks. Serial blood samples for pharmacokinetic analysis were collected at specified times over 24 hours after each dose of vitamin A for determination of serum concentrations of retinol, and over a period of 5 days after each dose of vitamin E for determination of serum concentrations of alpha-tocopherol, total cholesterol, and triglycerides. Orlistat significantly reduced the absorption of vitamin E (approximately 43% according to maximum concentration and approximately 60% according to area under the concentration-time curve), but not that of vitamin A, at the dose levels studied. The results of this study will aid in the implementation of a vitamin supplementation strategy, should vitamin deficiency occur in patients undergoing orlistat therapy.

Absorption↗

PubMed2003

Limited influence of P-glycoprotein on small-intestinal absorption of cilostazol, a high absorptive permeability drug.

Intestinal transport of the type III phosphodiesterase inhibitor cilostazol was characterized to evaluate the influence of secretory transporter. Intestinal absorption of cilostazol measured by the in situ closed loop method, showed regional differences, with high permeability in the upper part of the small intestine. Intestinal secretory transport of cilostazol at the ileum was tended to be decreased by the increase of tested concentration of cilostazol from 10 to 20 microM when evaluated by means of a Ussing-type chamber method with mounted rat intestinal tissues. Transcellular transport of cilostazol in the basolateral-to-apical direction in LLC-GA5-COL150 cells, which overexpress P-glycoprotein, was higher than that in parental LLC-PK1 cells. In addition, cilostazol reduced the basolateral-to-apical transport and increased the accumulation of [(3)H]daunomycin in LLC-GA5-COL150 cells. Accordingly, cilostazol was demonstrated to be transported by P-glycoprotein, while cilostazol is not likely to cause induction of the expression level of P-glycoprotein by the same manner with rifampin. Apical-to-basolateral transport of cilostazol in Caco-2 cells was increased in a low concentration range, followed by a decrease with further increase of the concentration, while the permeability coefficient of cilostazol was above 1 x 10(-6) cm/s at any concentration. Initial uptake of [(14)C]cilostazol by Caco-2 cells was temperature dependent and was reduced in the presence of unlabeled cilostazol, suggesting that apical uptake is also mediated by a transporter(s). In conclusion, intestinal absorption of cilostazol, which has a high absorptive permeability, may not be significantly hampered by efflux transporters, such as P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1978

GI absorption of beta-lactam antibiotics II: deviation from pH--partition hypothesis in penicillin absorption through in situ and in vitro lipoidal barriers.

The absorption of propicillin from the rat stomach and small intestine in situ was examined as a function of recirculating solution pH. The in vitro interphase transport from an aqueous buffer of various pH values to the octanol phase was also studied for several penicillins by the use of a two-phase rolling cell. The rate--pH profiles obtained from both in situ and in vitro experiments deviated significantly from the dissociation curves. The degrees of the shifts were approximately 2 pH units for the in situ intestinal absorption of propicillin and in vitro transport of propicillin and cloxacillin, approximately 1.5 pH units for the in vitro transport of penicillin V, and 0.8 pH unit for the in situ stomach absorption of propicillin. These discrepancies from the classical pH--partition hypothesis can be interpreted by the permeation through the lipoidal barrier of the undissociated species of penicillins transported through the aqueous diffusion layer adjacent to the lipoidal surface. All in situ and in vitro experiments tend to support this theory.

Animals↗

PubMed1983

Studies on the absorption of practically water-insoluble drugs following injection VIII: comparison of the subcutaneous absorption rates from aqueous suspensions in the mouse, rat, and rabbit.

Subcutaneous drug absorption rates from aqueous suspensions were measured in the mouse and the rabbit by a local clearance method and compared with those in the rat. A plot of the cube root of the residual fraction (W/W0) of the drug at the injection site versus time (t) gave a good linear relationship for the former two species. This implied that the kinetic equation for the absorption process in the rat, (W/W0)1/3 = 1 - jt, could be applied to them. In addition, the absorption rate constants (j) of the mouse and rabbit were close to that of the rat when the drug concentration (C0) in the suspension and the injection volume (V0) were fixed. These results led to the presumption that the correlation between j and C0 or V0 in the mouse and rabbit might be similar to that in the rat, and therefore, drug plasma levels for the former two at any dose might be roughly predictable even from one j value of the rat. The validity of this assumption was confirmed by comparison of the observed and predicted plasma concentrations after different subcutaneous doses of aqueous suspensions of N1-acetylsulfamethoxazole in the mouse and rabbit. These findings strongly supported the idea that for the subcutaneous administration of the drug in aqueous suspension under fixed dose per body weight, the rate of bioavailability should decrease with animal size, and therefore, the plasma drug level in larger species is not likely to be as high as that expected, from the data obtained for smaller species.

Absorption↗

PubMed1985

Drug absorption from inhalation aerosols administered by positive-pressure ventilation. II: Effect of disodium fluorescein aerosol particle size on fluorescein absorption kinetics in the beagle dog respiratory tract.

Solid, polydispersed disodium fluorescein aerosols (MMDae = 1.1, 3.5, and 4.4 micron) were administered under the same respiratory regime, direct to the respiratory tracts of two beagle dogs by positive-pressure ventilation. Subsequent to aerosol administration, plasma fluorescein concentrations were determined after sampling from an indwelling cannula. The amount absorbed as a function of time was estimated from these and additional data collected from intravenous control experiments in the same animals. Fluorescein absorption from the respiratory tract was apparently a first-order process, the rate increasing directly with the bioavailable dose. First-order rate constants differed but appeared unrelated to aerosol particle size, possibly reflecting similarities in their regional deposition in the canine lung. The average value for the absorption half-lives in the dogs were 19.3 and 12.2 min, showing that even lipophobic solutes such as the fluorescein dianion, are absorbed extremely rapidly via the lung. In one dog, the rate constant for fluorescein absorption after intratracheal instillation of a solution of the disodium salt was within the range of those following aerosol administration. Possible explanations are discussed.

Absorption↗

PubMed1989

Characterization of the oral absorption of beta-lactam antibiotics. II. Competitive absorption and peptide carrier specificity.

The beta-lactam antibiotic oral absorption pathway is studied using a single-pass perfusion technique in the rat small intestine. Beta-lactam antibiotic absorption in the presence of amino acids, small peptides, and other beta-lactams is modeled using a simple competitive inhibition boundary condition at the intestinal wall, with a corrected value for the intestinal wall concentration, Cw, derived from the modified boundary layer analysis. The model-predicted permeability in the presence of an inhibitor is used to characterize the beta-lactam antibiotic intestinal carrier system. Several concentrations of cephalexin, coperfused with a constant concentration of cefadroxil (equal to its Km), showed that the Km of cephalexin approximately doubled from 7.2 (+/- 1.1) to 18.8 (+/- 4.1) mM; Jmax remained unchanged at 9.2 (+/- 1.2) and 11.1 (+/- 2.1) mM; and the carrier permeability, Pc, was reduced by approximately 50% from 1.11 (+/- 0.10) to 0.59 (+/- 0.04), consistent with competitive absorption kinetics. The predicted in situ wall permeability, the mean value of P*w, of beta-lactams perfused in the presence of other beta-lactams was calculated and then compared with experimentally determined values. For cefadroxil, P*w = 0.27 (+/- 0.04), the mean value of P*w = 0.29; for cefatrizine, P*w = 0.67 (+/- 0.09), the mean value of P*w (+/- 0.09), the mean value of P*w = 0.59; and for cephalexin, P*w = 0.56 (+/- 0.05), the mean value of P*w = 0.59.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1990

Mechanism of nasal absorption of drugs. III: Nasal absorption of leucine enkephalin.

The nasal absorption of a model peptide, leucine enkephalin (LE), was studied in rats using an in situ technique in which 4 mL of perfusion solution was circulated. Leucine enkephalin (LE) was found to undergo hydrolysis to its major metabolite des-tyrosine leucine enkephalin (DTLE). The addition of 1% sodium glycocholate (SGC) to the perfusion solution resulted in an increase in the overall rate of disappearance of LE and a decrease in the rate of formation of DTLE. When LE was added to nasal washings (i.e., Ringer's buffer that was precirculated through the nasal cavity to extract enzymes), LE was found to form DTLE. When SGC or puromycin was added to the nasal washings prior to the addition of LE, the rate of conversion of LE to DTLE was significantly reduced, suggesting that these two agents can inhibit peptidase enzyme activity in the nasal cavity. Since the volume of the solution has been shown to influence the kinetics of absorption of drugs administered nasally, a new experimental technique, the in vivo-in situ technique, which utilizes small volumes of solution and simulates realistic use of nose drops, was employed to further examine the mechanism of absorption and hydrolysis of LE in rats. Leucine enkephalin (LE) dissolved in 100 microL of Ringer's buffer was placed in the isolated nasal cavities of rats. The disappearance of LE and the appearance of DTLE were followed by rinsing the nasal cavity with fresh buffer. Disappearance of LE was always accompanied by appearance of DTLE, and the fraction of LE converted to DTLE decreased as the concentration of LE increased, suggesting a saturable enzymatic process.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

PubMed1989

Proximal small intestinal mucosal injury. Maintenance of glucose and glucose polymer absorption, attenuation of disaccharide absorption.

The effect of chronic intragastric infusion of hypertonic mannitol on small intestinal mucosal structure and function was studied in adult rats. Animals were gavage-fed 20% mannitol (1300 mosm) at a dose of 5 ml/100 g body weight daily for seven days. Control animals were gavage-fed tap water on the same schedule. On day 8, the animals were anesthetized, the duodenum cannulated, and a test sugar (glucose, glucose polymer, lactose, sucrose, or maltose) was infused at a dose of 0.5 g/kg body weight in 2.5 ml distilled water over less than 1 min. Portal vein glucose was measured at 30-min intervals from 0 to 120 min. Mannitol treatment resulted in histologic and biochemical alterations (reduced lactase, sucrase, maltase) limited to the proximal small intestine compared to the control group. The absorption of glucose and glucose polymers was similar in mannitol-treated and control animals. In contrast, digestion and absorption of lactose, sucrose, and maltose was significantly diminished in mannitol-treated animals when compared to controls. No changes in permeability to polyethylene glycol 4000 or Na+-coupled glucose transport were observed in mannitol-treated animals compared to controls. These data suggest that when the intestinal mucosa is exposed to hyperosmolar loads that the digestive capacity for disaccharides is suppressed more than its glucose absorptive capacities. Furthermore, glucose oligomers may be more readily digested and absorbed than disaccharides, in this setting, due, in part, to the proximal injury and less pronounced proximal-distal gradient for glucoamylase than other brush-border carbohydrases.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Intestinal absorption of unconjugated dihydroxy bile acids: non-mediation by the carrier system involved in long chain fatty acid absorption.

Experiments were performed using isolated mucosal cells from the rat jejunum or using the perfused jejunum in the anesthetized rat to test whether lipophilic unconjugated dihydroxy bile acids are absorbed from the proximal small intestine via the same carrier mechanism involved in the uptake of long chain fatty acids. With isolated jejunal mucosal cells, the cellular uptake rate of deoxycholic acid or chenodeoxycholic acid increased linearly with time, showed no evidence of saturation, and was not decreased by the presence of a monospecific antibody to the membrane fatty acid binding protein. In contrast, oleate uptake was saturable, was inhibited by the same antibody, but was not affected by the presence of chenodeoxycholic acid or deoxycholic acid. Bile acid uptake by isolated enterocytes occurred at one-eighth the rate of fatty acid uptake if expressed in relation to total solute concentration; if expressed in relation to monomeric concentration, initial bile acid uptake was four orders of magnitude slower than fatty acid uptake. In the isolated perfused jejunal segment, chenodeoxycholic acid and deoxycholic acid uptake was not influenced by the presence of the antibody to membrane fatty acid binding protein, whereas absorption of oleate was inhibited by more than 70%. These experiments indicate that absorption of unconjugated lipophilic dihydroxy bile acids in the rodent jejunum does not involve the carrier mediated uptake mechanism involved in the absorption of long chain fatty acids--the mechanism is likely to be passive nonionic diffusion.

Animals↗

PubMed2005

The use of a sum of inverse Gaussian functions to describe the absorption profile of drugs exhibiting complex absorption.

PURPOSE: The aim of this study was to evaluate the utility of a parametric deconvolution method using a sum of inverse Gaussian functions (IG) to characterize the absorption and concentrations vs. time profile of drugs exhibiting complex absorption. METHODS: For a linear time-invariant system the response, Y(t), following an arbitrary input function I(t), is the convolution of I(t) with the disposition function, H(t), of the system: [Formula: see text]. The method proposed uses a sum of n inverse Gaussian functions to characterize I(t). The approach was compared with a standard nonparametric method using linear splines. Data were provided from previously published studies on two drugs (hydromorphone and veralipride) showing complex absorption and analyzed with NONMEM. RESULTS: A satisfactory fit for hydromorphone and veralipride data following oral administration was achieved by fitting a sum of two or three IG functions. The predictions of the input functions were very similar to those using linear splines. CONCLUSIONS: The use of a sum of IG as opposed to nonparametric functions, such as splines, offers a simpler implementation, a more intuitive interpretation of the results, a built-in extrapolation, and an easier implementation in a population context. Disadvantages are an apparent greater sensitivity to initial value estimates (when used with NONMEM).

Algorithms↗

PubMed1980

Selective effects of thiazide therapy on serum 1 alpha,25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciurias.

The effect of long-term thiazide therapy (hydrochlorothiazide, 50 mg twice/day) on intestinal calcium (Ca) absorption and serum 1 alpha,25-dihydroxyvitamin D [1 alpha,25-(OH)2D] concentration was examined in 10 patients with renal hypercalciuria (RH), many of whom had hyperabsorption of Ca, and in 11 cases of absorptive hypercalciuria (AH), all of whom had intestinal hyperabsorption of Ca. In patients with RH, the intestinal Ca absorption decreased significantly during thiazide therapy (mean treatment period of 15 mo) from 0.68 +/- 0.09 SD to 0.56 +/- 0.10 (p less than 0.01), commensurate with the "correction" of the renal leak of Ca and secondary hyperparathyroidism. Furthermore, serum 1 alpha,25-(OH)2D decreased significantly from 5.2 +/- 2.2 SD ng/dl to 3.7 +/- 0.8 ng/dl (p less than 0.025) during thiazide therapy. In patients with AH, the intestinal hyperabsorption of calcium persisted during thiazide treatment (0.69 +/- 0.07 versus 0.69 +/- 0.06), despite restoration of normal urinary Ca. Serum 1 alpha,25-(OH)2D was virtually unchanged during treatment (4.5 +/- 1.4 ng/dl versus 4.7 +/- 0.9 ng/dl). The results support the hypothesis that the intestinal hyperabsorption of Ca in RH is a result of increased serum concentration of 1 alpha,25-(OH)2D secondary to the hyperparathyroid state, while that in AH may not be totally dependent on increased concentrations of 1 alpha,25-(OH)2D.

Adult↗

PubMed1993

The isolated perfused bovine udder as an in vitro model of percutaneous drug absorption. Skin viability and percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate.

Using udders from slaughtered cows as a new in vitro model of percutaneous drug absorption, the tissue viability and the percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate were studied. The organ was perfused with gassed tyrode solution for up to 6 hr. As shown by measurement of glucose consumption, lactate production, lactate dehydrogenase activity, and pH in the perfusate, the tissue was viable over a 6-hr period. This was confirmed by a histological examination. Determination of the udder skin-fold thickness demonstrated that no edema developed within the perfusion period. A maximum skin penetration of dexamethasone was found after administration of dexamethasone dissolved in acetone with dimethyl sulfoxide, followed by ointment with salicylic acid, ointment without salicylic acid, and acetone solution. Experiments with benzoyl peroxide and etofenamate demonstrated that the perfused udder skin was capable of metabolizing drugs in vitro. In conclusion, the isolated perfused bovine udder is a new in vitro model, which maintains bovine udder skin with an isolated vasculature in a viable state. Using this in vitro model, we note it is possible to compare the dermal penetration, metabolism, and absorption of substances after topical administration of different drug formulations.

Animals↗

PubMed2005

Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers.

The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (beta-cyclodextrin, hydroxypropyl beta-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model. These AEs were found to enhance intestinal permeability of drugs from 2- to 27-fold. Light microscopy studies of intestinal sac incubated with AEs for 120 min revealed morphological changes in absorptive mucosa and rank order of toxicity were cyclodextrins>bile salts congruent with medium chain fatty acids. Fluorescence polarization studies indicated that brush bordered membrane vesicles labeled with lipophilic (DPH, 12AS) and hydrophilic dyes (ANS), when treated with AEs exhibited concentration and time dependent decrease in fluorescence polarization. Total protein released in presence of AEs was more than control but considerably less than EDTA (0.58% w/v), which is known to cause toxic release of proteins from cell. Overall, AEs were found to significantly enhance drug permeability by decreasing lipid membrane fluidity and/or interacting with hydrophilic domains of membrane, and has the potential to improve oral delivery.

Animals↗

PubMed2005

Prediction of oral drug absorption in humans by theoretical passive absorption model.

The purpose of the present study was to examine the oral drug absorption predictability of the theoretical passive absorption model (TPAM). As chemical descriptors of drugs, the octanol/buffer distribution coefficient at pH 6.0 (D(ow)), intrinsic octanol-water partition coefficient (P(ow)), pK(a), and molecular weight (MW) were calculated from the chemical structure. Total passive intestinal membrane permeation consists of transcellular, paracellular and unstirred water layer (UWL) permeation. Transcellular permeation was modeled based on the pH-partition hypothesis with correction for cationic species permeation, and the independent variables were D(ow), P(ow), and pK(a). Paracellular permeation was modeled as a size-restricted diffusion within a negative electrostatic field-of-force, and the independent variables were MW and pK(a). UWL permeation was modeled as diffusion across a water layer, and the independent variable was MW. Cationic species permeation in the transcellular permeation model and the effect of a negative electric field-of-force in the paracellular permeation model were the extensions to the previous TPAM. The coefficients of the paracellular and UWL permeation models were taken from the literature. A data set of 258 compounds with observed values of Fa% (the fraction of a dose absorbed in humans) taken from the literature was employed to optimize four fitting coefficients in the transcellular permeation model. The TPAM predicted Fa%, with root mean square errors of 15-21% and a correlation coefficient (CC) of 0.78-0.88. In addition, the TPAM predicted the effective human intestinal membrane permeability with a CC of 0.67-0.77, as well as the contribution of paracellular permeation. The TPAM was found to predict oral absorption from the chemical structure of drugs with adequate predictability for usage in drug discovery.

Administration, Oral↗

PubMed2001

DMT1 gene expression and cadmium absorption in human absorptive enterocytes.

Divalent metal transporter 1 (DMT1) is a transmembrane, proton-coupled metal ion transporter that is upregulated in the duodenum of iron-deficient rodents and in hereditary hemochromatosis patients, suggesting that it may constitute a key factor in the uptake of dietary iron. Functional expression studies in Xenopus oocytes have shown that DMT1 not only mediates transport of iron but also other divalent metal ions, including the toxic metal cadmium. In the present study, the correlation between the cadmium absorption process and gene expression of DMT1 was investigated in an experimental model of human absorptive enterocytes. Fully differentiated Caco-2 cells were grown in monolayers and treated with iron supplemented medium or control medium for 1, 3 or 7 days. At each time point, cadmium transport experiments across the Caco-2 cell monolayers were performed and gene expression of DMT1 measured. Iron treatment for 3 and 7 days resulted in a 50% reduction in the cadmium uptake and a 75% reduction in the transport of the metal across the basolateral membrane. No effects were observed at 24 h. Gene expression of DMT1 in the iron-treated Caco-2 cells was reduced by about 50% at 3 and 7 days and thus, correlated well with the uptake of cadmium. In summary, our results indicate that the uptake of cadmium into human absorptive enterocytes may be mediated by DMT1.

Animals↗

PubMed2001

Comparative absorption and variability in absorption of estradiol from a transdermal gel and a novel matrix-type transdermal patch.

OBJECTIVES: To compare the absorption of estradiol from a transdermal gel and a novel matrix-type patch and to study the variability in absorption. METHODS: Twenty-four healthy postmenopausal women were treated in an open, randomized, cross-over study for 18 days with 1.0 mg estradiol daily as a transdermal gel and a transdermal patch releasing estradiol 50 microg/24 h without a wash-out between the periods. Venous blood samples for estradiol pharmacokinetics were taken on the 15th and 18th study days of the gel period and during the 15th-18th study days during the patch period. RESULTS: There was no significant difference in peak estradiol level or area under the estradiol time-concentration curve between the gel and the patch. However, trough estradiol concentration was significantly lower and fluctuation higher with the patch. Estradiol time-concentration curves on the 15th and 18th study days with the gel were almost superimposable. A significant difference was observed in peak estradiol levels, whereas area under the curve or trough estradiol level did not differ between the 15th and 18th study days with the gel. Inter- and intra-individual coefficients of variability were around 30% for peak estradiol level and area under the curve, except for the intra-individual coefficient of variability for area under the curve (21%) for the gel. The total coefficient of variability for area under the curve was 35% for the gel and 39% for the patch. CONCLUSIONS: A daily 1.0 mg estradiol dose as a transdermal gel seems to correspond with a matrix-type patch releasing 50 microg estradiol daily in the extent of estradiol absorption. High variability was associated with both treatments, and both the variabilities within and between the subjects were high with the gel. Wider than generally applied confidence limits should be applied for bioequivalence testing of transdermal estradiol formulations.

Absorption↗

PubMed2006

Computational prediction of oral drug absorption based on absorption rate constants in humans.

Models for predicting oral drug absorption kinetics were developed by correlating absorption rate constants in humans (K(a)) with computational molecular descriptors. The K(a) values of a set of 22 passively absorbed drugs were derived from human plasma time-concentration profiles using a deconvolution approach. The K(a) values correlated well with experimental values of fraction of dose absorbed in humans (FA), better than the values of human jejunal permeability (P(eff)) which have previously been used to assess the in vivo absorption kinetics of drugs. The relationships between the K(a) values of the 22 structurally diverse drugs and computational molecular descriptors were established with PLS analysis. The analysis showed that the most important parameters describing log K(a) were polar surface area (PSA), number of hydrogen bond donors (HBD), and log D at a physiologically relevant pH. Combining log D at pH 6.0 with PSA or HBD resulted in models with Q(2) and R(2) values ranging from 0.74 to 0.76. An external data set of 169 compounds demonstrated that the models were able to predict K(a) values that correlated well with experimental FA values. Thus, it was shown that, using a combination of only two computational molecular descriptors, it is possible to predict with good accuracy the K(a) value for a new drug candidate.

Administration, Oral↗

PubMed1990

The molecular weight dependence of nasal absorption: the effect of absorption enhancers.

A series of polyethylene glycols (PEGs) ranging in molecular weight from near 600 to over 2000 daltons was used to study the effects of three absorption enhancers (sodium glycocholate, sodium lauryl sulfate, and polyoxyethylene 9 lauryl ether) on the molecular weight permeability profile of the nasal mucosa of the rat. Molecular weight-permeability properties were studied both by following changes in the excretion of the polyethylene glycols as a function of their molecular size and by examining the nasal mucosa for morphologic changes following exposure to the PEG/enhancer mixtures. Each absorption enhancer was found to affect the mucosa and its permeability in a unique manner. At a 1% concentration, sodium glycocholate only slightly affects tissue morphology and does not significantly alter the molecular weight permeability profile of the mucosa. In contrast, 1% sodium lauryl sulfate causes severe alteration of the mucosa and also greatly increases the absorption of both the PEG 600 and the PEG 2000 oligomers. Polyoxyethylene 9 lauryl ether was found to exert its action in a concentration-dependent manner. At a concentration of 0.1%, few changes were seen in either mucosal integrity or permeability. At a 1% concentration, however, a significant alteration in the structure of the mucosal tissues as well as a profound increase in the permeability of the mucosa to the PEGs was observed. Correlation of mucosal integrity with the effectiveness of an enhancer indicates that some of these compounds appear to be acting by altering the structure of the mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗