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R B Sund

Publications and source records attributed to R B Sund.

At least 37 records · Page 2Linked to original sources
PubMed1987

1-Naphthol metabolism and metabolite transport in the small and large intestine. II: Effect of sulphate and phosphate ion omission, and of 2,6-dichloro-4-nitrophenol in the isolated guinea pig mucosa.

A previous study (Sund & Lauterbach 1986) in the isolated guinea pig mucosa showed a complex pattern of 1-naphthol (I) metabolism and metabolite (glucuronide = II and sulphate = III) transport in relation to tissue studied (jejunum and colon) and administration side (lumen versus blood side). In the present paper aspects of I metabolism and II and III transport have been further studied. The experiments involved: Omission of inorganic sulphate in the incubation solution at one particular side or at both sides, to see if and how intestinal sulphoconjugation depended on side of sulphate ion entry, and if II and III efflux might be linked to sulphate ion influx. Similar omission experiments with inorganic phosphate, and Incubation in presence of 2,6-dichloro-4-nitrophenol (IV), a drug claimed to be a selective inhibitor of sulphoconjugation. The experiments showed: In the jejunum, sulphate ion caused a much stronger stimulation of III formation from the lumen than from the blood side, when I was added at the luminal side. In the colon, however, the sulphate ion was more effective on the blood side than on the lumen side, regardless of side at which I was added. More experiments are needed to clarify if conjugate efflux is affected by sulphate ion omission as well. Omission of inorganic phosphate did neither affect I metabolism nor II and III efflux. IV (present at both sides at once) had complex effects, involving inhibition of II and III synthesis as well as their efflux, and, in part, a change in their normal lumen: blood distribution pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Studies on laxatives: biliary and urinary excretion in rats given danthron by intravenous infusion or gastric intubation.

Rats were infused with danthron (I) at doses of 0.48, 2.2 and 5.8 mumol/100 g body weight, or given 12 mumol/100 g with gastric tube. TLC of bile and urine demonstrated a number of metabolites, at both administration routes. These included I monosulphate (II) and -glucuronide (III), two other phase 2 metabolites which behaved as the corresponding diconjugates, and several phase 1 metabolites (IV) in conjugated form. IV as a group were estimated by photometry of hydrolysed samples, using I as a reference. Danthron conjugates as a group were determined in such samples by a specific method for I. Moreover, II and III were determined individually in unhydrolysed specimens. Following infusion, about 80% of the danthron conjugates in bile were excreted after 1 hour; the dose fractions found after 5 hours represented about 20%, 30%, and 40% at the low, intermediate and high dose level, respectively. The corresponding fractions in urine were 16%, 12% and 10%, giving rise to bile:urine excretion ratios of 1.3, 2.7 and 4.0, respectively. This change in excretion pattern was associated with changes in metabolite muster, which involved a decrease in the balance of IV:I conjugates, as well as an increase in III:II ratio. IV was more abundantly present in bile than in urine, and showed a more sustained excretion than the I conjugates. By intragastric administration, the cumulated excretion (bile + urine) of I conjugates were only 6%, 8% and 5% of dose, in three consecutive 6 hours' periods (0-6, 6-12 and 12-18 hours after dosing). The bile:urine excretion ratios seemed to decrease with time, as did the III:II ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Drug metabolism and metabolite transport in the small and large intestine: experiments with 1-naphthol and phenolphthalein by luminal and contraluminal administration in the isolated guinea pig mucosa.

The metabolism and metabolite transport of the monophenol 1-naphthol (I) and the diphenol phenolphthalein (II) have been studied in a symmetrical setup of the isolated jejunal and colonic mucosa from the guinea pig (Lauterbach 1977). In both tissues, the main metabolites of I were its sulphoconjugate and glucuronide, but the rate of metabolism, relative proportion of the metabolites and their distribution pattern varied with tissue and drug administration side in the following manner: By luminal administration (50 nmol/ml) in the jejunum, the metabolism was nearly complete within 45 min., more sulphate (1.5-3x) than glucuronide was formed, and both metabolites were predominantly transferred back to the lumen. By blood-side administration, the metabolism was less complete due to a significant decrease of the sulphated fraction. In consequence, more glucuronide (1.5-3x) than sulphate was formed. Moreover, the efflux pattern of the metabolites changed completely; the greater part of the glucuronide fraction now being conveyed to the blood side, whereas the sulphate tended to distribute in a 1:1 fashion on the lumen and blood side. The colonic mucosa behaved in a dissimilar way, since neither I metabolism nor metabolite efflux pattern in this tissue was influenced significantly by drug administration side. More sulphate (1.5-3x) than glucuronide was formed by both routes, and the metabolite distribution was similar to that observed by blood side administration in the jejunum. The changes described above were associated with changes in tissue accumulation of free I and metabolites; accumulation of I by luminal administration in jejunum was insignificant and that of the metabolites small. The main change caused by a higher concentration of I (130 nmol/ml) was a decrease in the sulphated fraction in the colon. II was metabolized at a slower rate than I, and a significant tissue accumulation of free II was observed in all instances. The monoglucuronide was the main metabolite. Only minor amounts of II monosulphate were formed, making its distribution pattern difficult to ascertain. The distribution of II monoglucuronide on the other hand was generally similar to that described for its I analogue.

Animals↗
PubMed1984

Studies on hydragogue drugs: light and electron microscopic examination of the isolated rat colonic mucosa exposed to deoxycholic acid and synthetic surfactants.

Sacs of the stripped and everted, isolated descending rat colon were incubated for 2 hours in presence of the following surfactants at the mucosal side: Dodecylsulphate (DDS), dioctylsulphosuccinate (DOSS), cetrimonium bromide (CTMAB), Triton X100 and deoxycholic acid (DOC). After tissue fixation, the sacs were processed for light microscopy (LM) and for scanning (SEM) and transmission (TEM) electron microscopy. All three methods revealed that DOSS (1.3 X 10(-4) and 2.6 X 10(-4) mol/l, CTMAB (5 X 10(-5) and 1 X 10(-4) ) and Triton (2 X 10(-5), 5 X 10(-5) and 1 X 10(-4) ) caused only minor or moderate changes compared to parallel controls, as did also DDS at 1 X 10(-5) and 2 X 10(-5) mol/l. DDS at 2 X 10(-4) and 4 X 10(-4) mol/l and DOC at 1.5 X 10(-4) and 3 X 10(-4) mol/l caused more prominent changes. LM showed swollen, vacuolated cells with pycnotic nuclei; many of these cells seemed to be extruded. According to SEM, cells thus affected were most abundantly localized to the normal extrusion zone at the borders of the crypt-surface epithelial cell units. DOC tended to cause a more generalized affection within the units than DDS. In spite of these deleterious effects, gaps corresponding to missing epithelial cells were not observed. TEM indicated the mechanism responsible for restoration of epithelial continuity in spite of extensive cell loss: The remaining epithelial cells seemed to flatten out and re-establish cell-to-cell contact by pseudopod formation along the basement lamina. This repair mechanism seemed to operate at a rapid rate; however, incomplete closure of cellular gaps i.e. small denuded parts of the basement lamina were occasionally observed. The results of this study are discussed in relation to a functional study under identical experimental conditions (Gastroenterol. Clin. Biol. 1981, 5, 124), in which these surfactants caused a significant alteration of normal colonic transport function.

Animals↗
PubMed1982

Biliary excretion of bisacodyl and picosulphate in man: studies in gallstone patients after biliary tract surgery.

Bisacodyl (=BIS) and picosulphate (=PICO) have been given perorally to postoperative gallstone patients, who have undergone biliary tract surgery with the insertion of an indwelling T-tube. The doses corresponded to 7.7 mg of their common free diphenol desacetylbisacodyl (=DES). The bile was sampled in hourly fraction from the external limb of the T-tube; these fractions were analysed by a modification of the HPLC method previously used to study biliary excretion in the rat. In the BIS-patients (n=8), DES in conjugated form occurred in significant concentration already in the first fractions; peak excretion values equivalent to 4-8 microgram DES/ml bile were reached in 2-5 hours. Unchanged BIS could not be detected, and the concentration levels of unconjugated DES were insignificant. The PICO-patients (n=8) on the other hand showed low DES concentrations (conjugated + free less than or equal to 0.5 microgram DES/ml) in all fractions, or low initial concentrations followed by a more or less pronounced rise in the later fractions. These results are, qualitatively, as in the rat. However, the dose fractions excreted in bile (assuming a total hepatic output of 50ml/hours) seem smaller than those to be expected from rat experiments, at least as far as BIS is concerned.

Adult↗
PubMed1982

Interaction between diphenolic laxatives and intestinal bacteria in vitro.

The ability of the laxative diphenols desacetylbisacodyl, oxyphenisatin, and phenolphthalein to inhibit growth and cause leakage of potassium ion from microbial cells in vitro was studied with 25 aerobic and 25 anaerobic bacterial strains. None of the aerobes, but some of the anaerobes showed growth inhibition. Potassium release assayed by flame photometry was observed in strains which showed growth inhibition, but also in other strains including anaerobes and aerobes. The highest antibacterial activity among the diphenols was observed with phenolphthalein and the least with desacetylbisacodyl; this relationship as noted for both growth inhibition and potassium release. Enzymatic hydrolysis of picosulphate to the free diphenol desacetylbisacodyl carried out by three strains of anaerobic bacteria was indicated by high pressure liquid chromatography.

Bacteria↗
PubMed1982

Uptake, conjugation and transport of laxative diphenols by everted sacs of the rat jejunum and stripped colon.

Phenolphthalein (PHEN), desacetylbisacodyl (DES) and oxyphenisatin (OXY) were incubated with everted sacs of the rat jejunum and stripped descending colon; the mucosal and serosal fluid were analysed with respect to free and conjugated diphenol by means of HPLC. Conjugates were measured as the amount of free diphenol in completely hydrolyzed samples less the amount before hydrolysis. A study with double-sided administration of PHEN revealed that diphenol uptake from and conjugate output to both sides followed a rectilinear course for 15-90 min. A standard incubation time of 60 min. was chosen for the subsequent experiments, in which the diphenols were administered at the mucosal side at a low and a high concentration. Diphenol uptake, i.e. the amount of free diphenol administered less the amount recovered at the mucosal side, varied in an order (PHEN greater than DES greater than OXY) which seems to be inversely related to the order of water solubility of the compounds. Tissue accumulation and conjugate output relative to uptake varied with the dose, and from one compound to another. At low initial concentration (20 nmol/ml), the compounds were transferred to the jejunal and colonic serosal fluid almost entirely as conjugates (greater than or equal to 95%); the transfer rates followed, qualitatively, the same order as above. In jejunum, more conjugates were released to the mucosal than to the serosal side; in colon the distribution was reversed. Increasing the dose to 100 nmol/ml caused a corresponding increase in uptake, but relative output decreased and tissue accumulation increased; thus demonstrating capacity limitation. With PHEN, the ratio of conjugated:free diphenol on the serosal side remained essentially unchanged; with DES in particular, but also with OXY the ratio decreased. These findings may be interpreted to mean that in case of PHEN capacity limitation is linked to conjugate efflux, while DES and OXY may be poor substrates for glucuronide formation as well. Experiments with serosal side administration like the double-sided PHEN experiments verified the dissimilar conjugate distribution in jejunal and colonic sacs; the phenomenon is to some extent discussed in the text. Identity tests gave evidence that the conjugates were mainly monoglucuronides.

Animals↗
PubMed1982

Intestinal handling of bisacodyl and picosulphate by everted sacs of the rat jejunum and stripped colon.

Bisacodyl (BIS) is the acetic acid di-ester of the laxative diphenol 2-(4,4'-dihydroxydiphenyl)methyl-pyridine. A HPLC-method which permits the simultaneous determination of BIS and its monodesacetylated (MONO) as well as totally desacetylated (DES) form, has been used to study the intestinal handling of BIS (20 nmol/ml), when the compound was incubated for 60 min. at the mucosal side of the preparations specified. In the jejunal mucosal fluid, BIS disappeared completely in short time, and there was a nearly equivalent rise in DES. MONO was transitory present. Hydrolysis was also rapid in mucosal fluid which had been in contact with jejunal sacs for 30 sec., but BIS was stable in blank incubations. Hydrolysis of BIS was slower by colonic than by jejunal sacs, and all three molecular forms were present during incubation. It seemed still slower in mucosal fluid which had been in contact with colonic sacs for 5 min. BIS just as DES accumulated in the jejunal and colonic serosal fluid mainly as conjugates (greater than 95%), and DES was in all cases the only unconjugated metabolite present. Drug accumulation in jejunal serosal fluid was the same whether BIS or DES was added. However, more drug seemed to accumulate on the serosal side of colonic sacs when incubated with BIS instead of DES. In similar experiments with picosulphate, which is the sulphuric acid di-ester analogue of BIS, free DES was not detected in the mucosal fluid during incubation. The amounts of laxative accumulating in the serosal fluid were less than 1/10 of those observed with BIS.

Animals↗
PubMed1981

Studies on hydragogue drugs: effect of surfactants on cAMP levels in the rat jejunal mucosa in short time experiments in vivo.

Theophylline and the surface active agents specified below were instilled into the jejunum of anaesthetized rats, and the cAMP levels in the mucosal tissue determined after 71/2 and 15 min. incubation in vivo. Most experiments were done in rats prepared with two tied intestinal loops; one of these served as the control loop and the other as the stimulated loop. The surfactants (mmol/l) included dodecylsulphate (17), dioctylsulphosuccinate (5.6), cetrimonium bromide (4.1), deoxycholic acid (2.4 and 3.6) and Lubrol WX (0.5% w/v). Theophylline (10 mmol/l) caused a substantial increase in cAMP (110% +/- 17, n = 7 and 60% +/- 8.9, n = 10, respectively) and dodecylsulphate a minor and transitory increase (28.1% +/- 3.8, n = 10 and 11.7% +/- 4.9, n = 8). The other agents were without stimulatory effect on cAMP, although like dodecylsulphate they may significantly affect normal intestinal cation and glucose transport under these conditions. The results, therefore, do not suggest that stimulation of cAMP and intestinal secretion induced thereby is any significant phenomenon in the overall hydragogue effect of these agents, at least not in short term jejunal experiments.

Animals↗
PubMed1981

Enterohepatic circulation, urinary excretion and laxative action of some bisacodyl derivatives after intragastric administration in the rat.

Bisacodyl (BIS), the parent diphenol (DES) and its sulphuric acid di-ester (picosulphate = PICO) were given by stomach tube to fasted rats at a dose of 3.1 mumol/100 g rat. Bile was sampled in the periods 0-6, 6-12 and 12-18 hrs after drug administration, and assayed for total diphenol (= free + conjugated) by HPLC. Mean fractions (% of dose +/- S.E.M.) excreted in 5 rats per compound and period were: BIS 74.0 +/- 4.7, 51.9 +/- 7.9 and 30.8 +/- 2.5; DES 41.2 +/-4.3, 46.8 +/- 4.7 and 25.1 +/- 2.5; PICO 9.0 +/- 0.9, 26.0 +/- 5.4 and 19.6 +/- 3.1. Only minor amounts were excreted as free diphenol. Urine samples taken by bladder puncture and assayed as above furthermore showed that the renal excretion of total diphenol was insignificant compared to the amounts excreted in bile. Practically no diphenol was present in urine 0-6 hrs after the administration of PICO. In experiments with BIS and DES at 0.85 mumol/100 g, total diphenol excreted in bile during 0-6 hrs was: BIS 67.1 +/- 2.6 (n = 5); DES: 55.4 +/- 3.0 (5). - The latency time for laxative effect was studied in groups of 10 unfasted rats per compound. cumulative time response curves showed that PICO caused diarrhoea more promptly at 0.85 mumol/100 g than either BIS or DES. In most rats, this delayed action of BIS and DES persisted also at 1.7 mumol/100 g. At 3.1 mumol/100 g, however, the majority of the rats reacted as promptly to these two compounds as to PICO. These results are discussed in relation to the biliary excretion experiments, and interpreted in terms of the relative importance at the different dose levels of: 1. The enterohepatic recirculated fraction, and 2. The non-absorbed fraction, which passes directly to the large intestine. For PICO, the latter fraction is the single determinant of the effect, which is triggered when the di-ester is being hydrolyzed to active diphenol in this part of the GI-tract.

Animals↗
PubMed1978

Glucose and cation transport in rat jejunum, ileum and colon in vivo: control experiments, and effect of cationic surfactant.

Osmotically balanced solutions of glucose (0.5-300 mM) and sodium chloride, containing cetrimonium bromide (cetrimide, 0.8-4.1 mM), were instilled into the jejunum, ileum and colon of anaesthetized rats. Net transport of glucose, sodium and potassium was studied by their disappearance from, or accumulation into the intestinal lumen during 15 min incubation. Cetrimide caused the following shifts in normal jejunal and ileal glucose absorption: At low luminal glucose levels, absorption was strongly depressed and may be converted to net secretion. At intermediate levels, inhibition was less pronounced, and at high luminal glucose levels absorption was enhanced. Similar changes were seen in the colon. Furthermore, cetrimide caused a three-fold change in the regression lines relating net sodium fluxes to the initial sodium concentration: The lines became steeper, the correlation was improved and the sodium concentration value corresponding to zero net transport was elevated. Net potassium secretion was increased. These changes are all consistent with the view that surfactants cause an increase in passive permeability. Quantitatively, the effect of cetrimide increased with localization in the order colon greater than ileum greater than jejunum. Benzalkonium chloride (0.5-1.7 mM) was tested in the ileum only, and caused quite similar effects.

Animals↗
PubMed1978

Glucose and cation transport in rat jejunum, ileum and colon in vivo: effects of anionic and nonionic surfactants, and of desoxycholate.

Osmotically balanced solutions of glucose (0.5--300 mM) and sodium chloride, containing surfactants, were instilled into the small or large intestine of anaesthetized rats. Net absorption or secretion of glucose, sodium and potassium was studied. The surfactants tested were dodecylsulphate (3.4--17 mM), dioctylsulphosuccinate (1.8--11 m/M), Lubrol WX (0.1--5%), Triton X 100 (0.25%) and desoxycholate (2.5 mM). Qualitatively, the results were similar to those obtained previously with cationic compounds, suggesting a common mode of action for all surfactants studied. 17 mM dodecylsulphate seemed to abolish completely physiological glucose transport in the jejunum and ileum. At a lower concentration, and witth the other surfactants, normal glucose transport was affected to an intermediate extent.

Animals↗
PubMed1978

Intestinal secretion of sulphanilic acid by the isolated mucosa of guinea pig jejunum.

Tissue uptake and transepithelial permeation of 35S-sulphanilic acid were studied in the isolated guinea pig jejunal mucosa. Methoxy-3H-inulin added simultaneously served as a marker for the extracellular space and permeability of paracellular shunt pathways in the preparation. The uptake of sulphanilic acid from the blood side exceeded that from the luminal side 4--7 fold. The permeation of the acid was strongly correlated to the permeation of inulin. At 5 micrometer and 2.5 mM sulphanilic acid under aerobic conditions, the regression lines for the permeation from lumen to blood pass almost through the origin, while the regression lines for the permeation from blood to lumen intersect the ordinate at a positive Y-value. In anaerobiosis, at 25 mM sulphanilic acid, or with addition of p-toluene sulphonic acid only one regression line is obtained for the permeation in both directions. It is concluded that besides a permeation of sulphanilic acid across inulinpermeable shunt pathways an active transport system exists, which transfers the acid from the blood to the luminal side. This system is saturable, depends on aerobic energy and exhibits mutual inhibition by a structurally related compound. The results are comparable to those previously obtained with cardiac glycosides and quaternary ammonium compounds, in the same preparation. Thus, the intestinal mucosa is able to secrete the same classes of compounds which are secreted by the liver and the kidney.

Aerobiosis↗
PubMed1978

In vivo reversibility of the jejunal glucose and cation transport alteration caused by intraluminal surfactants in the rat.

Tied jejunal loops in anaesthetized rats were under standardized conditions pre-exposed for 30 min. with Tyrode solution containing surfactants. 5, 20 or 150 min. after wash out of bulk surfactant, the loops were re-instilled with Tyrode containing glucose at 5--15 mmol/l. Net glucose, sodium and potassium transport were studied for 15 min. by changes in intraluminal amounts, and compared with results obtained in control rats. The surfactants (mmol/l) tested were the anionics dioctylsulphosuccinate (5.6) and dodecylsulphate (8.5--17), the cationics cetrimonium bromide (2.1--4.1) and benzalkonium chloride (2.1), the nonionics Triton X100 (0.25%) and Lubrol WX (0.25--0.5%) plus cholic acid (4.9) and desoxycholic acid (1.3--2.5). In most cases, the glucose transport was normal or fairly normal after 150 min., most of the restoration taking place shortly after surfactant removal. However, Lubrol in particular caused more irreversible effects. Generally, the changes in net cation transport tended to be less easily reversible than the alteration in glucose transport. In so far as a normal or near to normal glucose transport is unlikely to occur unless both functional and structural integrity of the epithelium is preserved, the results indicate that in most cases there is but insignificant epithelial damage under the experimental conditions. Since, furthermore, these surfactants can interact with glucose transport in the same technique even at lower concentration and shorter incubation time than used here, it is concluded that the interaction of surfactants with intestinal transport is not neccessarily linked to gross histo-pathological changes.

Animals↗