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PubMed1998

A general approach for the prediction of the intestinal absorption of drugs: regression analysis using the physicochemical properties and drug-membrane electrostatic interaction.

A general method for predicting the intestinal absorption of a wide range of drugs using multiple regression analysis of their physicochemical properties and the drug-membrane electrostatic interaction was developed. The absorption rates of tested drugs from rat jejunum were measured by the in situ single-pass perfusion technique. The drugs used in this study were divided into three groups for regression analysis, and a smaller "test" set of compounds was used to assess the predictive capacity of the regression equation. When the analysis was applied to each respective group of drugs (i.e., anionic, cationic, and nonionized compounds), obtained regression coefficients were 0.569, 0.821, 0.728 by using the organic solvent (n-octanol)/buffer partition coefficient, 0.730, 0.734, 0.914 using the permeation rate across a silicon membrane, and 0.790, 0.915, 0.941 using an EVA membrane, respectively. However, smaller regression coefficients of 0.377, 0. 468, and 0.718 were obtained when these three groups of drugs were put together for prediction. Meanwhile, correlation was improved remarkably when drug-membrane electrostatic interactions, namely, hydrogen-bonding donor (Halpha) and acceptor (Hbeta) activity or index of electricity (Ec), were added to the other parameters of lipophilicity and permeation rate across the EVA membrane (r = 0.880 and 0.883, respectively). Moreover, the equation obtained from these regression analyses was applicable even to the prediction of the absorption of the zwitterionic drugs. These results suggest that including the electrostatic interaction parameters in addition to lipophilicity and permeability across artificial membranes would afford a better prediction for the intestinal absorption of the vast majority of drugs.

Animals↗
PubMed1992

Intestinal absorption of peptides and peptide analogues: implications of fasting pancreatic serine protease levels and pH on the extent of oral absorption in dogs and humans.

In order to describe and predict the impact of intestinal metabolism on peptide absorption, intestinal chymotrypsin activity, flow rate, and pH were characterized in fasted, duodenally fistulated dogs as a function of gastrointestinal (GI) motility phase. GI motility was classified as either active or quiescent. Cumulative volume, F(t), and volumetric flow rate, Q(t), curves were constructed and the data were sorted according to motility phase. The mean +/- SE active phase pH was 6.4 +/- 0.3, whereas the quiescent phase pH was 7.3 +/- 0.3. The difference between the mean active and the mean quiescent phase pH values was significant. The active and quiescent phase flow rates (ml/min) were also significantly different, at values of 1.2 +/- 0.2 and 0.28 +/- 0.07, respectively. The active phase flow rates were consistent among the dogs studied; however, the quiescent phase flow rates were highly variable among the dogs. The variability of the quiescent phase flow rates was expected since phase II of the GI motility cycle is characterized by intermediate, irregular spike activity. The mean active and quiescent phase chymotrypsin activities were 1.87 x 10(-5) +/- 0.53 x 10(-5) and 1.56 x 10(-5) +/- 0.65 x 10(-5) M, respectively. The active phase values were not statistically different among dogs, however, the quiescent phase values were found to be highly variable among dogs. The difference between the active and the quiescent phase chymotrypsin mean levels, however, was not statistically significant. The chymotrypsin levels determined in dogs were found to be approximately 10 times greater than those reported in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1984

Intestinal absorption of manganese in experimental malnutrition.

We investigated possible changes in mechanisms of the intestinal absorption of Mn in rats malnourished with a low protein-low energy diet (M) for 4 weeks against controls fed a complete diet (C) during the same period. The absorption of Mn in the absence or in the presence of two small molecular weight ligands, citrate and L-histidine, was studied by an in vivo procedure. In both M and C rats, jejunal Mn absorption decreased linearly with time and was enhanced by the presence of the low molecular weight ligands. The initial rate of absorption, for Mn alone, was higher in M than in C rats, but it was indistinguishable between both groups in the presence of either citrate or L-histidine. Total Mn absorption, in midperfusion, was greater in M than in C animals with no ligands in the solutions (means +/- SEM, M = 2,969 +/- 923 vs. C = 654 +/- 218 pmol/cm, p less than 0.05). However, in the presence of citrate or L-histidine, the well-nourished rats absorbed more Mn than M rats. Also, water fluxes across the mucosa had a positive correlation with Mn transport when the ligands were present. This solvent drag of the trace element was not operant in the absence of citrate or L-histidine. These data indicate that the jejunal mucosa of M rats absorbs Mn more effectively than C animals, independently from water fluxes and the presence of small molecular weight chelators. These substances do not alter the uptake of Mn in growth-retarded rats, while they enhance the absorption of the trace metal in well-fed animals.

Animals↗
PubMedDate not supplied

Intestinal absorption of S-(pentachlorobutadienyl)glutathione and S-(pentachlorobutadienyl)-L-cysteine, the glutathione and cysteine S-conjugates of hexachlorobuta-1,3-diene.

The bioactivation of the nephrotoxin hexachlorobuta-1,3-diene (HCBD) involves hepatic formation and biliary excretion of S-(pentachlorobutadienyl)glutathione (PCBG). The intestinal absorption of PCBG was studied in vivo by introducing PCBG or its metabolite, S-(pentachlorobutadienyl)-L-cysteine (PCBC), into rat intestines via a biliary cannula and measuring PCBG and PCBC concentrations in portal blood. When PCBG was infused into the intestine, both PCBG and PCBC were found in the blood; the highest metabolite concentrations (0.9 nmol/ml for PCBG and 1 nmol/ml for PCBC) were observed 30 min after infusing the S-conjugate. Higher blood PCBC concentrations were observed after PCBC infusion than after PCBG infusion. Transport studies in CaCo-2 cells, a human intestinal cell line, showed that application of PCBG (0.1 mM) to the apical side of the cells resulted in a 2.4-fold accumulation of PCBG in the basolateral chamber after 24 hr; in this time, the cells metabolized 69% of the applied PCBG to PCBC. Addition of glutathione (1 mM), gamma-glutamyl-p-nitroanilide (1 mM), or probenecid (1 mM) to the apical chamber diminished the active transport of PCBG. With PCBC, no active apical or basolateral transport was observed. The experiments are the first demonstration of the intestinal absorption of the S-conjugates of HCBD, which is an important step in their translocation from the liver to the kidney.

Animals↗
PubMed1982

Disposition, intestinal absorption and drug metabolizing enzyme activities after multiple doses of indomethacin in rat and effect of antacid and dicyclomine on the parameters.

The effect of repeated treatment with indomethacin (IND) on the disposition and intestinal absorption of the drug and microsomal drug-metabolizing enzyme activities were studied in comparison with coadministration of the drug and magnesium silicate or dicyclomine in male Wistar rats. The plasma decay curve of IND following a rapid i.v. injection (6 mg/kg) was found to be biexponential. The elimination rate constant (beta) of beta phase was 0.138 +/- 0.015 h-1. The beta after the multiple dosing of IND (6 mg/kg/d for 7 d, p.o.) was significantly decreased as compared with that after a single dosing. In the multiple dose group coadministered magnesium silicate (0.6 g/kg), the AUC0 leads to infinity was 2 times that after the multiple dosing of IND alone. The repeated administration (8 times every 16 h) with IND (4 mg/kg) alone and IND plus the antacid respectively gave the results similar to those in the multiple dosing. In the multiple treated group with IND alone, the drug-metabolizing enzyme activities were significantly decreased (32-43%) as compared with the control, however, the coadministration of magnesium silicate partly protected the decrease. The intestinal absorption rate constant of IND determined by in situ method was decreased after the multiple dosing of IND alone, but the constant was recovered to the control value after coadministration of the antacid. Following the multiple dosing of IND alone, the centrilobular necrosis in liver and a partial omission of the villi of intestinal epithelium were observed, but the concurrent dosing of magnesium silicate did not produce histopathological changes.

Animals↗
PubMed1997

Intestinal absorption of Mn-mesoporphyrin in a small bowel sac system: effect of oleic acid.

RATIONALE AND OBJECTIVES: The authors investigated the effect of oleic acid (cis-9-octadecenoic acid) (OA), a lipidic carrier, on the intestinal absorption rate and T1 relaxation time of manganese (III) mesoporphyrin (Mn-mesoporphyrin), a prototype hepatobiliary contrast agent for magnetic resonance imaging. METHODS: Mn-mesoporphyrin was formulated with OA at various concentrations. Small bowel sacs were created in 36 rats and filled with complexed and free Mn-mesoporphyrin. Intestinal absorption of Mn-mesoporphyrin was measured with spectrophotometry at 364 nm. T1 relaxation times were measured in samples of Mn-mesoporphyrin solutions, bowel wall, liver, and bile. RESULTS: Absorption rates ranged from 4.2%/cm2/h to 13%/cm2/h. Absorption was greatest (13%/cm2/h) when a combination of 1 mmol/L Mn-mesoporphyrin and 26.5 mmol/L OA was used. The T1 of bile decreased from 2,480 to 248 msec (maximum decrease) in rats that received Mn-mesoporphyrin. CONCLUSION: Mn-mesoporphyrin is absorbed from the small bowel in both the lipid-associated and free form, resulting in substantial shortening of the T1 in bile.

Animals↗
PubMed1997

Intestinal absorption of sodium dodecyl sulfate in the rodent: evidence for paracellular absorption.

Experiments were performed to define the mechanism of intestinal absorption of dodecyl sulfate (DS), an amphipathic organic anion whose chemical structure resembles that of dodecanoate, a C12 fatty acid anion. With jejunal segments perfused in single-pass fashion in the anesthetized rat, steady-state absorption of DS was concentration dependent, with the apparent permeability constant (P(app)) ranging from 4 to 22 x 10(-5) cm/s. When DS concentration was held constant and net water absorption was induced by decreasing perfusate osmolality, DS absorption increased in direct proportion to water absorption, suggesting absorption by solvent drag via the paracellular route. However, DS absorption continued even when water secretion was induced by a hypertonic perfusate. Consequently, for all experiments, DS absorption could be empirically described as the sum of two terms: 1) absorption in the absence of water absorption (P(app) = 5.6 x 10(-5) cm/s) and 2) absorption induced by water movement [(delta P(app)/delta water absorption) = 0.2 x 10(-5) cm x s(-1) x microl segment(-1) x min(-1)]. In a polarized epithelial monolayer of renal epithelial cells (Madin-Darby canine kidney cells), DS was absorbed predominantly by a paracellular pathway, as the absorption rate increased threefold when paracellular junction pore size was increased by the addition of cytochalasin D. The calculated apparent radius was 2.9 A, indicating that the cross section of the molecule, not its length, determined the rate of absorption. It is concluded that absorption of DS in the intact animal occurs slowly and mostly via the paracellular route, because the fixed negative charge on the molecule retards rapid passive entry into the enterocyte, as occurs with protonated fatty acids. That absorption of DS persisted despite net water secretion suggests a low level of transcellular absorption across the jejunal enterocyte also occurs.

Animals↗
PubMed1988

Intestinal absorption of phosphatidylcholine and triglyceride after ileal resection.

The intestinal absorption of (14C)oleoyl moieties in triglyceride and phospholipid was investigated by means of (14C)phosphatidylcholine and (14C)triolein breath tests. In patients who had undergone ileal resection the absorption of both phosphatidylcholine and triglyceride was subnormal, as reflected by a lower production of 14CO2. In healthy subjects the production of expiratory 14CO2 after oral administration of (14C)phosphatidylcholine was slightly higher than after administration of (14C)triolein. This was also observed in the patient group, indicating that the absorption of both triglyceride and phospholipid was decreased to similar extents, although triglyceride absorption tended to be more affected after major ileal resection. In patients with lipid malabsorption the proportion of linoleic acid in serum phosphatidylcholine was subnormal, and the decrease was correlated to the decrease in lipid absorption. The concentration in serum of selenium, alpha-tocopherol, and carotene but not of ascorbic acid and retinol was subnormal after ileal resection.

Adolescent↗
PubMed1995

Influence of anesthetic regimens on the intestinal absorption of 5-fluorouracil in rats.

We investigated the influence of anesthetic regimens on the intestinal absorption of 5-fluorouracil (5-FU), which is known to be absorbed by concurrent Na(+)-dependent, carrier-mediated transport and passive transport, in single-pass perfusion experiments in rats. Compared with the absorption in unanesthetized rats, the regular dose of urethane (1.13g/kg) reduced the maximum transport rate (Jmax), the Michaelis constant (Km) and the membrane permeability coefficient of passive transport (P m,d); a low dose of urethane (0.7g/kg) reduced Jmax and Kmax, but did not affect Pm,d; pentobarbital sodium (50 mg/kg) increased Jmax without affecting Km, and reduced Pm,d. The reductions in Jmax and Km were comparable for the regular and low doses of urethane. Thus, urethane and pentobarbital, which have been most commonly used in laboratory animal experiments, exerted qualitatively different effects on the carrier-mediated transport of 5-FU, although they similarly inhibited the passive transport. For urethane, the effect on the passive transport was avoided by reducing the dose, but the effect on the carrier-mediated transport was not. This influence of anesthetic regimens on intestinal drug absorption may not be easily scaled for normalizing absorption data. When compiling them for such purposes as establishing in situ-in vivo quantitative correlation, the absorption data in perfusion (in situ) should be categorized on the basis of anesthetic regimens, to avoid ending up with poor outcomes. We also examined the effect of urethane on the exsorption of Na+ in the intestinal loop where Na+-free buffer was introduced, and found a minimal effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1988

Prediction of the effect of ofloxacine on intestinal absorption: effect of the body weight and substrate concentration.

1. The effect of body weight and initial concentration on the rat small intestinal absorption of DL-8280 (ofloxacine) is studied using a recirculating perfusion technique and an improved HPLC method. 2. A prediction equation is developed under statistical and physiological considerations which correlates both factors with the intestinal absorption rate parameter Kapp.

Animals↗
PubMed1989

Intestinal absorption of oxalate and calcium in patients with jejunoileal bypass.

Jejunoileal bypass (JIB) has been widely performed for treatment of excessive obesity. Formation of calcium oxalate stones is a common side effect. Since, under physiological conditions, the intestinal absorption of calcium and that of oxalate are interrelated, intestinal oxalate and calcium absorption were measured in the present study by isotope techniques in 19 JIB patients and 20 healthy controls. The JIB patients showed pronounced hyperoxaluria and markedly increased absorption of oxalate, with a urinary excretion of 14C-oxalate of 29 +/- 19% (controls 6.2 +/- 3.7%; p less than 0.001). There was a strong correlation between the intestinal absorption and urinary excretion of oxalate in the JIB patients (r = 0.72; p less than 0.001). Furthermore, their oxalate kinetics was altered, with continued urinary excretion of 14C-oxalate for up to 48 hours. The JIB patients also had reduced calcium absorption (36 +/- 9.1% vs. 47 +/- 9.0%; p less than 0.001) and patients with malabsorption of calcium and low urinary calcium had the highest intestinal absorption and urinary excretion of oxalate. It is concluded that hyperoxaluria in JIB patients is due to a significant extent to hyperabsorption of oxalate.

Adult↗
PubMed1994

Tea extract inhibits intestinal absorption of glucose and sodium in rats.

The effect of tea extract on the intestinal absorption of glucose and sodium was studied in rats. Tea extract reduced the mucosal uptake of glucose and its portal plasma concentration, but was without any effect on its serosal transport. The mucosal uptake of sodium was similarly inhibited. The tea extract reduced also the in vitro activity of the Na(+)-K+ ATPase in an intestinal mucosal homogenate. These data are consistent with the hypothesis that an active ingredient in tea reduced sodium extrusion from the enterocytes by inhibiting the Na(+)-K+ pump, thus destroying the gradient needed for the mucosal transport of glucose.

Animals↗
PubMed1996

Effect of iron status on the intestinal absorption of aluminum: a reappraisal.

Clinical and experimental studies have shown that serum aluminum (Al) is bound to transferrin and that cellular uptake of Al appears to be mediated by transferrin receptors. Based on these findings it is widely believed that intestinal Al absorption occurs via iron-specific, transferrin-dependent pathways and that iron (Fe) deficiency increases the intestinal absorption of Al. However, since no transferrin receptors are expressed on the absorptive surface of small intestinal epithelial cells this notion is doubtful. To further clarify the issue the present study investigated the effect of marked alterations of body Fe stores on the intestinal absorption of Al using three different rat models. (I) Serum Al concentrations and urinary excretion rates of Al were measured in iron-overloaded (Fe+) or iron-deficient (Fe-) rats with either normal (C) or impaired (5/6 nephrectomy) renal function (Nx) employing oral A1 loads in single dose studies. (II) Tissue A1 accumulation as well as serum and urine A1 were determined in respective experimental groups exposed to a prolonged (41 days) dietary Al load. (III) To assess the effect of Fe status on the intestinal absorption of Al directly at the organ level perfusions of in situ rat gut preparations were performed. In the single dose studies administration of Al resulted in similar urinary excretion rates of Al in intact kidney groups (C+Fe-, 229 +/- 85 nmol/5 days; C+Fe+, 240 +/- 59 nmol/5 days) despite marked differences in liver Fe (C+Fe-, 1.34 +/- 0.16 vs. C+Fe+, 55.69 +/- 13.20 mumol/g) and duodenal mucosal Fe (C+Fe-, 0.68 +/- 0.11 vs. C+Fe+, 3.17 +/- 0.82 mumol/g). In addition, mucosal Al concentration 24 hours after the load was not affected by the Fe status (C+Fe-, 37 +/- 16 nmol/g, C+Fe+, 56 +/- 19 nmol/g). Regardless of the Fe status post-load Al excretion was enhanced in Nx rats (Nx+Fe-, 533 +/- 234 nmol/five days, Nx+Fe+, 536 +/- 201 nmol/five days). Irrespective of Fe status a prolonged dietary Al load resulted in a similar increase in tissue Al concentration (nmol/g) in liver (baseline, 159 +/- 22; C+Fe-, 276 +/- 125; C+Fe+, 251 +/- 71; Nx+Fe-, 330 +/- 119; Nx+Fe+, 437 +/- 67) and in bone (baseline, 219 +/- 119; C+Fe-, 433 +/- 174, C+Fe+, 485 +/- 141; Nx+Fe-, 504 +/- 185; Nx+Fe+, 548 +/- 215). The increase in spleen Al was significantly larger in Fe-overloaded rats (baseline, 194 +/- 20; C+Fe+, 511 +/- 129 vs. C+Fe-, 308 +/- 62, P < 0.05; Nx+Fe+, 514 +/- 67 vs. Nx+Fe-, 389 +/- 119, P < 0.05). Brain Al tended to rise in Nx rats only (baseline, 96 +/- 33; Nx+Fe+, 174 +/- 100, Nx+Fe-, 156 +/- 78, P = NS). Analogous results were obtained in in situ intestinal perfusion studies: Fe deficiency and Fe overload both did not affect the time-dependent increase in serum Al in either systemic or portal vein blood. When paracellular intestinal permeability was assessed mannitol absorption was significantly higher in uremic animals as compared to controls. Pharmacological blockade (2 mM kinetin) of the paracellular permeability substantially reduced the time-dependent increase in serum Al in uremic rats but had little effect in control animals, suggesting that even the excess absorption of Al observed in uremia occurs via a paracellular rather than an iron-specific pathway. In conclusion, the findings of the present study provide several lines of evidence against the commonly accepted view that the intestinal absorption of Al occurs via iron-specific pathways. Most likely, this is related to the fact, that neither the absorption of Fe nor the absorption of Al are mediated via transferrin receptors. In addition, the enhanced intestinal absorption of Al observed in uremic rats does also not occur via iron-specific pathways, but seems to due to increased paracellular permeability of the intestine.

Aluminum↗
PubMed1989

Use of the peptide carrier system to improve the intestinal absorption of L-alpha-methyldopa: carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-alpha-methyldopa.

Intestinal permeabilities of five dipeptidyl derivatives of L-alpha-methyldopa (I) were studied by an in situ intestinal perfusion method. The dipeptides displayed a significant increase in their permeabilities compared to L-alpha-methyldopa. The increases ranged from 4 to 20 times. These results suggest that the peptide transport system is less structurally specific than the amino acid transport systems and can be used as an absorption pathway for peptide analogues. The kinetic advantage demonstrated by the dipeptide, L-alpha-methyldopa-L-phenylalanine, over the amino acid analogue, L-alpha-methyldopa, suggests that the peptide carrier would be a possible route for improving the intestinal absorption of pharmacologically active amino acid analogues. Furthermore, the preliminary results of in vitro hydrolysis studies of selected dipeptidyl derivatives indicate that the peptide carrier system could be used as a base for a prodrug strategy.

Animals↗
PubMed1980

[Actidione-cycloheximide and the route of intestinal absorption of lipids in the rat].

The effect of actidione-cycloheximide on the intestinal absorption of 14C oleic acid was studied on male rats using the ex vivo perfusion technique in control rats and those treated with a protein synthesis inhibitor. With the amounts of lipid infused, the radioactivity recovered in portal blood lipids was the same in treated rats and in controls. However, differences were observed in the appearance of oleic acid in the portal blood during the first 15 min. When protein synthesis was inhibited, absorption occurred earlier via the portal blood. The absorption balance in this type of experiment was considerably lower than normal absorption probably because or surgical stress. In conclusion, when esterification was impaired, oleic acid seemed to be absorbed via the portal blood at the beginning of the experiment like short or medium-chain fatty acids.

Animals↗
PubMed1975

The influence of oral administered iron compounds on the intestinal absorption of immunoglobulin-G in newborn piglets.

The intestinal absorption of IgG from colostrum in newborn piglets was not disturbed by oral administration of iron preparations used for prophylactic treatment of anaemia in piglets. Iron dextran, ferrous fumarate or a combination of these compounds were administered simultaneously with the colostrum supply, soon after birth and the concentrations of IgG in serum were determined.

Administration, Oral↗
PubMed1984

Intestinal absorption of vitamin E in low birth weight infants.

Intestinal absorption of dl-alpha-tocopheryl acetate was studied in low birth weight infants. Vitamin E was given from the first day of life, either as a water-soluble (Ephynal) or as a lipid-soluble preparation (E-vitamin). Serum-alpha-tocopherol concentrations were determined before treatment and on days three and seven. Treatment with both vitamin E preparations increased serum-alpha-tocopherol on day three and seven. The mean serum-alpha-tocopherol +/- SD on day seven were 41.4 +/- 10.7 mumol/l for the Ephynal group and 26.7 +/- 12.5 mumol/l for the E-vitamin group, this difference being statistically significant (p less than 0.025). Oral feeding seems to influence the absorption of tocopherol from E-vitamin, as the infants with the highest serum-alpha-tocopherol concentrations were those with the highest oral/total feeding ratios. In infants with birth weight less than 1 000 g treatment with 25 mg Ephynal/day was found to increase serum-alpha-tocopherol on day seven to 46.9 +/- 12.3 mumol/l (mean +/- SD). This concentration is comparable to those reported by others using higher doses of oral vitamin E.

Humans↗
PubMed1987

Effect of allopurinol on the intestinal absorption of 6-mercaptopurine in rats.

The effect of allopurinol, a xanthine oxidase inhibitor, on the intestinal absorption characteristics of 6-mercaptopurine was investigated by in situ and in vitro absorption techniques in rats. In the in situ experiment, the percent disappearance of 6-mercaptopurine from the lumen showed a dependency on initial drug concentration. Most of the 6-mercaptopurine that was lost from the lumen appeared as its metabolite, 6-thiouric acid, in the lumen. Dose-dependency of 6-mercaptopurine disappearance from the lumen and the biotransformation of drug to 6-thiouric acid were not observed in the presence of allopurinol. The in vitro data supported the results of the in situ experiment. In addition, allopurinol increased the serosal transfer in vitro and the mesenteric appearance of 6-mercaptopurine in situ by inhibiting the biotransformation to 6-thiouric acid. These results suggested that the type of absorption characteristics observed with 6-mercaptopurine was due to its metabolism by xanthine oxidase in the intestine.

Allopurinol↗