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At least 19 recordsLinked to original sources
PubMed1990

Effect of pretreatment with antibiotics on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms.

The effect of pretreatment with antibiotics on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms was investigated. Latamoxef sodium (LMOX, 25 mg/kg/d, intravenously) and cephalexin (CEX, 16.7 mg/kg/d, orally) were administered for 1 or 3 d. The blood concentration of salicyluric acid and salicylic acid following oral, intracecal and rectal administration of salicyluric acid was determined. By the pretreatment with LMOX for 1 or 3 d, the blood concentration of salicylic acid following oral administration of salicyluric acid was slightly decreased. In rabbits pretreated with CEX for 3 d, the blood concentration of salicylic acid was detected at low concentration. By the pretreatment with LMOX and CEX, however, the decrease in the blood concentration of salicylic acid following rectal administration of salicyluric acid was not observed. Although the examination of population of intestinal microorganisms induced by the pretreatment with antibiotics was not performed, the metabolic activity of intestinal microorganisms may be changed.

Administration, Oral↗
PubMed1955

Formation of amines by intestinal microorganisms and the influence of chlortetracycline.

Although gastric and intestinal contents from rats failed to show amino acid decarboxylase activity when tested against five different amino acids (glutamic acid, arginine, lysine, tyrosine, and histidine), the feces contained at least seven different amines, some known to be pharmacologically active. Putrescine, histamine, and tyramine were identified by means of paper chromatography in both intestinal material and mixed fecal cultures; four other spots were found, three of which had Rf values similar to agmatine, ethanolamine, and ephedrine. The formation of lysine and glutamic acid decarboxylases was not enhanced by an increased acidity during growth while increased oxygen tension was inhibitory to amino acid decarboxylase synthesis in these fecal cultures. The feeding of chlortetracycline to rats, or its presence at a very low concentration in media in which the mixed cultures were grown, reduced the capacity of intestinal microorganisms to produce amines. Cells from mixed fecal cultures grown in the presence of chlortetracycline lacked or contained but weak amino acid decarboxylase activities. The action of the enzymes themselves was unaffected by the presence of the antibiotic in the Warburg cup during assay. The results suggest that amines formed within the intestinal tract might be toxic to the rat, and that chlortetracycline accelerates animal growth by suppressing their production.

Amines↗
PubMed1971

Vitamin B12 uptake by intestinal microorganisms: mechanism and relevance to syndromes of intestinal bacterial overgrowth.

The mechanism of bacterial uptake of vitamin B(12), the spectrum of microorganisms capable of such uptake, and the factors involved were the subject of this study. Bacterial uptake of vitamin B(12) was found to be at least a two stage process. A primary uptake phase which was rapid (1 min or less), pH dependent, nontemperature dependent, did not require viable organisms and was insensitive to either the metabolic inhibitor dinitrophenol or to the sulfhydryl inhibitor N-ethyl-maleimide. Protein denaturation (formalin treatment or autoclaving) abolished all B(12) uptake. This primary uptake phase is thought to represent adsorption to binding or "receptor" sites on the cell wall. Second stage uptake was slower, pH and temperature dependent, required living bacteria, and was abolished by either dinitrophenol or N-ethyl-maleimide. This phase is dependent upon metabolic processes and may reflect transfer of B(12) from surface "receptor" sites into the bacterial cell. Although differences among organisms were observed in total 1 hr uptake, number of surface "receptor" sites, and relative avidities for B(12), all organisms except Streptococcus fecalis shared the two stage mechanism. Two Gram-positive organisms. Bacillus subtilis and Group A streptococcus, demonstrated the highest 1 hr vitamin B(12) uptake values; Gram-negative bacteria required 2,000-10,000 the number of organisms for comparable uptake. Binding constants (K(m)) varied from 5.05 +/-1.67 x 10(-10)M for B. subtilis to 6.18 +/-3.08 x 10(-9)M for Klebsiella pneumoniae which approximate the Km for human intrinsic factor (0.38 x 10(-10)M). Competition between bacteria and intrinsic factor for vitamin B(12) may be inferred from the similarity of these constants. These observations suggest that a variety of enteric and nonenteric organisms, not requiring exogenous B(12), may play a role in the pathogenesis of the vitamin B(12) malabsorption found in the intestinal bacterial overgrowth syndromes.

Bacillus subtilis↗
PubMed1989

Effect of fasting on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms.

The effect of fasting on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms was investigated. The blood concentration of salicyluric acid and salicylic acid following oral, intracecal and rectal administration of salicyluric acid was determined. In fasted rabbits (24 and 48 h), the blood concentration of salicylic acid after oral administration was changed compared to the control. However, a significant effect of fasting was not observed in the blood concentration of salicylic acid after rectal administration. Following intracecal administration, the blood concentration of salicylic acid was increased in fasted rabbits compared to the control. From these results, it seems that the slow rate of stomach emptying due to coprophagy during fasting is the principal reason for the change of blood concentration of salicylic acid following oral administration of salicyluric acid.

Administration, Oral↗
PubMed1978

Formation of a mutagenic drug metabolite by intestinal microorganisms.

A new broad-spectrum antiparasitic agent, 4-isothiocyano-4'-nitrodiphenylamine, is devoid of mutagenic activity in vitro, either alone or in the presence of activating enzymes of rat liver. However, six species of mammals receiving this drug excrete as as yet unidentified mutagenic metabolite. Several observations suggested that one or several constituents of the enteric bacterial flora, rather than the metabolic activities of the host, are involved in the formation of this mutagen. Unequivocal demonstration for such a mechanism was provided by germ-free rats that do not form this metabolite, in contrast to their conventional littermates. Only a relatively moderate and apparently quite selective reduction in the total number of microorganisms of the intestinal flora is needed to elminate this mutagenic transformation. For example, following administration of a single dose of erythromycin or erythromycylamine, conversion of the isothiocyanate to a mutagen can be prevented completely, while antiparastitic activity is maintained. There is no obligatory association between chemotherapeutic activity and the formation of the mutagenic metabolite, and these two activities can be dissociated completely. This suggests a new approach for increasing the safety of pharmacological agents.

Animals↗
PubMed1999

Effects of DFA IV in rats: calcium absorption and metabolism of DFA IV by intestinal microorganisms.

Di-D-fructose-2,6':6,2'-dianhydride (DFA IV) is a disaccharide consisting of two fructose residues that can be prepared from levan by levan fructotransferase from Arthrobacter nicotinovorans GS-9, and it can be expected to have novel physiological functions from its unique structure. In this study, the effects of DFA IV on calcium absorption and the metabolism of DFA IV by intestinal microorganisms were studied in rats to examine the physiological functions of DFA IV. The apparent calcium absorption in rats fed with DFA IV was significantly higher than that in the control rats, and it seems that calcium absorption had almost been completed at the end of the small intestine. DFA IV also increased the calcium absorption in in vitro experiments, using everted jejunal and ileal sacs, and this result supports the finding obtained in the in vivo experiments. These results indicate that DFA IV may have a function for increasing the calcium absorption in the small intestine of rats. However, the effect in the large intestine could not be clearly observed because of the lack of calcium that reached there. The results of analyses of organic acids in the cecal and colonic contents and of DFA IV in the fecal, cecal, and colonic contents showed that the metabolism of DFA IV by microorganisms in the large intestine progressed gradually, and that DFA IV was converted mainly to acetate, butyrate, and lactate.

Animals↗
PubMed1994

Pharmacokinetic analysis of in vivo metabolism of amino acid or dipeptide conjugates of salicylic acid in rabbit intestinal microorganisms.

We analyzed the pharmacokinetics of salicylic acid (SA)-amino acid (alanine, glutamic acid, methionine, and tyrosine) or SA-dipeptide (glycylglycine) conjugates in rabbits, by using a model that takes into account the metabolism of prodrug to SA by intestinal microorganisms and, also, by model-independent analysis. The blood concentration profiles of these prodrugs and released SA following intracecal and oral administration to rabbits were obtained previously (Nakamura et al., J. Pharm. Pharmacol., 44, 295-299, 1992; Chem. Pharm. Bull., 40, 2164-2168, 1992; Int. J. Pharm., 87, 59-66, 1992; J. Pharm. Pharmacol., 44, 713-716, 1992). First, the overall in vivo behavior was evaluated by statistical moment analysis. Next, the blood concentration profiles of prodrug and SA following intracecal and oral administration were simultaneously fitted to the above model. In general, good agreement was observed between fitted lines and experimental data for every prodrug, suggesting the validity of this model. The obtained parameters characterized the difference in the rate of metabolism and absorption among the prodrugs. Lower absorbability and enhanced hydrolysis rate of the prodrug lead to prolonged blood concentration of SA.

Administration, Oral↗
PubMed2003

Transformation of flavonoids by intestinal microorganisms.

Fruit, vegetables and cereals contain a wealth of secondary plan metabolites which have been implicated in the promotion of health. To understand the mechanism of their action it is necessary to gain more information on their fate in the body following ingestion. A certain proportion of ingested secondary plant constituents may escape absorption in the small intestine and therefore undergo transformation by intestinal microorganisms or enterohepatic circulation. To study the transformation of secondary plant metabolites by bacteria, Eubacterium ramulus was isolated from human feces and incubated with selected flavonoids. E. ramulus is a strictly anaerobic bacterium which was found to be present in the gastrointestinal tract of most individuals investigated. E. ramulus cleaves the ring system of several flavonols and flavones giving rise to the corresponding hydroxyphenylacetic and hydroxyphenylpropionic acids, respectively, as well as acetate and butyrate. Degradation pathways were proposed based on the intermediates detected by high performance liquid chromatography (HPLC) and HPLC coupled with mass spectrometry (LC-MS) and the detection of enzymes that catalyze reactions such as taxifolin isomerization, phloretin hydrolysis and phloroglucinol reduction. The dearomatizing phloroglucinol reductase, presumably part of all flavonoid degradation pathways, was purified and characterized. The gene encoding phloretin hydrolase was cloned from a E. ramulus gene library taking advantage of a newly developed fluorescence test for activity screening. Moreover, a new intermediate was discovered and identified by MS and 1H and 13C NMR analysis as alphitonin. To investigate the degradational potential of E. ramulus under in vivo conditions, germfree rats were associated with E. ramulus. Following the intragastric application of quercetin-3-glucoside, urine and feces of gnotobiotic rats were analyzed for degradational products originating from quercetin-3-glucoside. In feces of rats monoassociated with E. ramulus, 3,4-dihydroxyphenylacetic acid was found, indicating that this organism is able to cleave quercetin under in vivo conditions. To investigate in which way the dietary flavonoid content affects the cell counts of E. ramulus in the human intestinal tract, twelve human subjects consumed a flavonoid-free diet for one week and at one point during this period a large dose of flavonoids. Fecal samples from both phases of the study were analyzed by in-situ hybridization for total bacterial counts and counts of E. ramulus. Total cell counts and the cell counts of E. ramulus decreased significantly during the flavonoid-free period, while there was an increase in the E. ramulus counts of up to 10-fold during the flavonoid-rich period indicating that dietary secondary plant metabolites may have an influence on the intestinal microflora. E. ramulus is also capable of converting the isoflavonoids genistein and daidzein to the products 2-(4-hydroxyphenyl)-propionic acid and O-desmethylangolensin, respectively.

Animals↗
PubMed1992

Effect of oral pretreatment with antibiotics on the hydrolysis of salicylic acid-tyrosine and salicylic acid-methionine prodrugs in rabbit intestinal microorganisms.

We examined the hydrolysis mechanism of salicylic acid-tyrosine (salicyl-tyrosine) and salicylic acid-methionine conjugate (salicyl-methionine) in rabbits by exploring their behavior following intraduodenal and intracecal administration (72 and 36 mumol/kg, respectively: salicylic acid equivalent). A large amount of salicyl-methionine was absorbed following intraduodenal administration of salicyl-methionine, without being metabolized to salicylic acid in the small intestinal mucosa. On the contrary, salicylic acid was detected in the blood following intraduodenal administration of salicyl-tyrosine, suggesting that salicyl-tyrosine was metabolized in the small intestinal mucosa. After oral pretreatment of rabbits with kanamycin sulfate (6 x 400 mg) or tinidazole (6 x 160 mg), the hydrolysis of salicyl-tyrosine and salicyl-methionine following intracecal administration was inhibited significantly, indicating that the intestinal microorganisms were responsible for the biotransformation of these prodrugs. Furthermore, in rabbits orally pretreated with both kanamycin sulfate and tinidazole, a significant inhibition of salicylic acid formation from salicyl-tyrosine and salicyl-methionine following intracecal administration was observed.

Animals↗
PubMed1998

Different pharmacokinetics of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-(3-14C)dithiazocine-4-carboxyli c acid between the fasting and non-fasting rat: role of intestinal microorganisms.

1. We report differences in the pharmacokinetics of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-(3-14C)dithiazocine-4-carb oxylic acid (14C-SA3443) between the normal fasting and non-fasting rat, especially in the blood concentration-time curves and respiratory excretion. Exhalation of 14CO2 was an important route of elimination and accounted for 21.2% of the dose in the non-fasting rat but only 3.7% in fasting animals. 2. In the intestinal microorganism-compromised rat, we found little differences in the pharmacokinetics of 14C-SA3443 between fasting and non-fasting states. No respiratory excretion was observed in the intestinal microorganism-compromised animal. 3. In the reaction mixture of 14C-SA3443 with the cecal contents of rat, 14C-acetic acid and 14C-butyric acid were detected and 14CO2 barely detected. 4. The amounts of 14C-acetic acid and 14C-butyric acid in the reaction mixture of 14C-SA3443 with non-fasting rat cecal contents were more than those with fasting rat cecal contents. 5. We concluded that the reason for the different pharmacokinetics of 14C-SA3443 between the fasting and non-fasting rat was the differences in participation of the metabolism of 14C-SA3443 by intestinal microorganisms.

Adjuvants, Immunologic↗
PubMed1992

Development of a prodrug of salicylic acid, salicylic acid-L-alanine conjugate, utilizing hydrolysis by rabbit intestinal microorganisms.

The hydrolysis of salicylic acid-L-alanine conjugate (salicyl-L-alanine) following oral, intravenous, intracaecal and rectal administration (60, 10, 5 and 5 mg kg-1, respectively: salicylic acid equivalent) was examined in rabbits. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-L-alanine and reached a maximum concentration at 10 h, whereas salicyl-L-alanine was rapidly eliminated. In contrast, unchanged salicyl-L-alanine only was found following intravenous administration of salicyl-L-alanine, suggesting that presystemic de-conjugation of salicyl-L-alanine was involved. The intestinal mucosal de-conjugation of salicyl-L-alanine was not recognized in the in-situ intestinal sac preparation with complete mesenteric venous blood collection. Immediate and very extensive salicylic acid formation in the caecum was found following intracaecal administration of salicyl-L-alanine. After oral pretreatment of rabbits with kanamycin sulphate, a significant inhibition of salicylic acid formation following intracaecal administration of salicyl-L-alanine was observed, indicating that the intestinal microorganisms were responsible for the biotransformation of salicyl-L-alanine. In-vitro incubation of salicyl-L-alanine with gut contents showed that the major source of its hydrolysis was the hind gut. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicyl-L-alanine, suggesting the usefulness of salicyl-L-alanine as a prodrug of salicylic acid.

Administration, Oral↗
PubMed1987

Maintenance nitrogen requirements and intestinal microorganisms in rats.

Nitrogen (N) balance trials with young growing rats fed diets with and without nonabsorbable antibiotics and with various concentrations of crude protein (CP) were conducted to measure maintenance N requirements. In addition, cecal contents were analyzed for ammonia (NH3), urea (U) and free amino acids (AA) to study the reduction in maintenance N requirements due to the action of antibiotics. Results of the N-balance trials verified the reduction in maintenance N requirements with antibiotics as described in the literature. The reduction, however, was not as large as previously demonstrated, possibly because of severe diarrhea and greater liquid accumulation in the cecum of rats fed antibiotics. The concentration of free AA and U in the postabsorptive region of the intestine (cecum) of rats consuming antibiotics was greater than when antibiotics were not consumed. Cecal N concentrations supported the concept that the mode of action of antibiotics in reducing maintenance N requirements was via reduced destruction of AA of body origin in the lower intestine. Cecal levels of NH3 were similar in both antibiotic and nonantibiotic groups. The amount of N needed for body maintenance when conditions favored minimum destruction of body AA by lower intestine microorganisms was small, less than 1% dietary CP. Maintenance N may be limited to the needs for tissues on the exterior of the body, such as hair, which are poorly recycled through the digestive tract.

Amino Acids↗
PubMed1992

A novel prodrug of salicylic acid, salicylic acid-glutamic acid conjugate utilizing hydrolysis in rabbit intestinal microorganisms.

The fate of salicylic acid-glutamic acid conjugate (salicyl-glutamic acid) following oral, intravenous, intracecal and rectal administration (60, 10, 5 and 5 mg/kg, respectively: salicylic acid equivalent) was examined in rabbits. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-glutamic acid and it reached the maximum level (69.4 micrograms/ml) at 18 h after the dose. A high blood concentration of salicylic acid (24.8 micrograms/ml) was observed up to 36 h. But only a small amount of salicyl-glutamic acid was detected in the blood (less than 2.5 micrograms/ml, as salicylic acid). In contrast, unchanged salicyl-glutamic acid was found mainly in the blood following intravenous administration of salicyl-glutamic acid, suggesting that presystemic de-conjugation of salicyl-glutamic acid predominantly occurred. The intestinal mucosal de-conjugation of salicyl-glutamic acid was negligible in the in situ intestinal sac preparation with complete mesenteric venous blood collection. Immediate and very extensive salicylic acid formation in the cecum was found following intracecal administration of salicyl-glutamic acid. After oral pretreatment of rabbits with kanamycin sulfate (6 x 400 mg), a significant inhibition of salicylic acid formation following intracecal administration of salicyl-glutamic acid was observed, indicating that the intestinal microorganisms were responsible for the biotransformation of salicyl-glutamic acid. Also, in vitro incubation of salicyl-glutamic acid with gut contents showed that the primary location of hydrolysis was the hind gut.

Animals↗
PubMed1992

A novel prodrug of salicylic acid, salicylic acid-glycylglycine conjugate, utilizing the hydrolysis in rabbit intestinal microorganisms.

The hydrolysis of salicylic acid-glycylglycine conjugate (salicyl-glycylglycine) following oral, intravenous, intracaecal and rectal administration (434, 72, 36 and 36 mumol kg-1, respectively: equivalent to salicylic acid) was examined in rabbits to develop a novel prodrug of salicylic acid. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-glycylglycine and it reached a maximum level (55.6 micrograms mL-1) at 15 h, whereas a small amount of salicyl-glycylglycine was found in the blood. In contrast, unchanged salicyl-glycylglycine was found mainly in the blood following its intravenous administration, suggesting the involvement of presystemic deconjugation in the hydrolysis of salicyl-glycylglycine. Immediate and very extensive salicyclic acid formation in the caecum was observed following intracaecal administration of salicyl-glycylglycine, suggesting that the intestinal microorganisms were responsible for the biotransformation of this compound. In-vitro incubation of salicyl-glycylglycine with caecal content showed that salicyl-glycylglycine was hydrolysed efficiently in the caecum. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicyl-glycylglycine, indicating the usefulness of salicyl-glycylglycine as a prodrug of salicylic acid.

Administration, Oral↗
PubMed1992

Unequal hydrolysis of salicylic acid-D-alanine and salicylic acid-L-alanine conjugate in rabbit intestinal microorganisms.

The behavior of salicylic acid-D-alanine conjugate (salicyl-D-alanine) following intravenous, oral and intracecal administration was examined in rabbits, then compared with that of salicylic acid-L-alanine conjugate (salicyl-L-alanine) as reported previously. Following intravenous administration, salicyl-D-alanine eliminated rapidly from the blood, and its blood concentration was almost identical with that of salicyl-L-alanine. In both cases, salicylic acid could not be detected in the blood, indicating that systemic de-conjugation of D-alanine might not occur. Unchanged salicyl-D-alanine was found in the blood mainly following oral and intracecal administration of salicyl-D-alanine. On the other hand, salicylic acid formed extensively following oral and intracecal administration of salicyl-L-alanine, suggesting that the presystemic de-conjugation of D-alanine and L-alanine was unequal. Furthermore, in vitro incubation of salicyl-D-alanine with cecal content, in which the major source of salicyl-L-alanine hydrolysis is found, showed that the hydrolysis of salicyl-D-alanine was negligible in rabbit intestinal microorganisms.

Administration, Oral↗
PubMed1997

Metabolism of azetirelin, a new thyrotropin-releasing hormone (TRH) analogue, by intestinal microorganisms.

PURPOSE: We evaluated the effect of luminal bacterial metabolism on intestinal absorption of azetirelin in rats. In vitro characteristics of bacterial metabolism of azetirelin were also investigated with the goal of overcoming the low stability of the peptidic drug against luminal microorganisms. METHODS: Plasma azetirelin levels after oral administration to antibiotic-pretreated rats was examined. In vitro incubation experiments with bacterial suspensions were also performed to clarify the location of azetirelin breakdown activity as well as the effects of oxygen, pH, and various protease inhibitors on drug metabolism. RESULTS: Plasma azetirelin levels were sustained after oral administration to antibiotic-treated rats. Incubation with rat luminal contents demonstrated that azetirelin was metabolized by anacrobic bacteria, which are predominant in the distal intestine. Fecal suspensions from rats, dogs, and humans showed comparable metabolic activity. Azetirelin breakdown in the bacterial suspension was pH-dependent and was inhibited in the presence of bacitracin or puromycin. CONCLUSIONS: Bacterial metabolism influences the degree of absorption of azetirelin in the distal intestine. Control of the luminal pH environment may be a practical method for improving the stability of azetirelin against intestinal microorganisms.

Animals↗