Intestinal Drug Absorption and Metabolism III: Glycine Conjugation and Accumulation of Benzoic Acid in Rat Intestinal Tissue

doi:10.1002/jps.2600600227

Journal of Pharmaceutical Sciences

Volume 60, Issue 2, February 1971, Pages 278-281

https://doi.org/10.1002/jps.2600600227 Get rights and content

Abstract

Glycine conjugation of ¹⁴C-benzoic acid to ¹⁴C-hippuric acid was demonstrated in in vitro rat intestinal slices and everted intestinal preparations. Hippuric acid was detected and quantified by two independent analytical techniques, a quantitative TLC method, and a reverse isotope dilution method. Comparison of hippuric acid concentration after 2 hr. in mucosal and serosal fluids when hippuric acid was formed endogenously from benzoic acid, and with mucosal and serosal concentrations when hippuric acid was added exogenously to the mucosal fluid, indicated that hippuric acid is formed in the tissue compartment rather than by bacterial or intestinal enzymes in the mucosal fluid. Hippuric acid is apparently formed enzymatically in the mucosal cell according to a previously proposed cell compartment model and subsequently diffuses to both mucosal and serosal fluids. The net amount of hippuric acid formed under the conditions of the study was small (about 1%) and was found to be due to limited synthesis rather than to extensive hydrolysis. Both exogenously added benzoic acid and hippuric acid accumulated in the intestinal tissue compartment (11.2 and 6.4%, respectively) during transfer from the mucosal fluid.

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Given that mitochondria are the place for Krebs cycle and are quite abundant in the brush border of the proximal tubules, the deficiency in the Krebs cycle activity may be seen as a mitochondrial dysfunction. Hippurate is synthetized by the conjugation of glycine and benzoate in the kidney but also in the liver and in the intestine (Poon and Pang, 1995; Strahl and Barr, 1971). As previously shown by Deguchi et al. in 2005, circulating hippurate molecules are mostly uptaken by the organic anion transporter 1 in rats (rOat1) located in the basolateral membrane of kidney.
Conjugation and excretion of metabolites of 7-hydroxycoumarin in the small intestine of rats and guinea-pigs
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7-Hydroxycoumarin is conjugated with glucuronic acid and sulphate in intestinal preparations of both rats and guinea-pigs. The highest activity was found at the oral end of the small intestine and the lowest activity at the aboral end. Some distributional differences between the glucuronyl transferase(s) and sulphotransferase(s) were observed. In both gut sacs and in situ preparations a considerable secretion of conjugate into the lumen was found; the significance of this finding to chemical toxicity in the lower gut is discussed.
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The metabolism of several foreign compounds has been investigated in viable isolated liver and intestinal mucosal cells. Glucuronic acid and sulphate conjugation was observed in both cell preparations with respect to phenol. Conjugation of 1-naphthol was also observed in isolated intestinal cells. Acetanilide was the only metabolic product of aniline observed with intestinal cells. N-Acetylation was also found to be the major pathway of aniline metabolism in liver cells but p-hydroxylation followed by O-conjugation were also important reactions. Intestinal cells thus appear to be generally effective in conjugation reactions. However, in contrast to hepatocytes the intestinal cells were unable to form glycine conjugates from benzoic acid. The metabolism of 7-ethoxycoumarin and 7-hydroxycoumarin was investigated in isolated intestinal cells from control, 3-methylcholanthrene and phenobarbitone pretreated rats. Glucuronic acid and sulphate conjugation rates of 7-hydroxycoumarin appeared to be unaffected by these pretreatments whereas increases in 7-ethoxycoumarin O-deethylation were observed.
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An in vitro model that utilizes everted rat intestinal sacs was evaluated for assessing the absorptivity of several analogs of potential drug substances prior to formulation work and clinical trials. This model not only is a useful qualitative tool for assessing absorptivity of structurally related compounds but also yields some insight into the process involved in drug absorption. Notwithstanding the complexities involved in the absorption processes, the data support the hypothesis that the absorption of organic electrolytes mainly takes place by the partitioning of the unionized species into the lipoidal membranes and then diffusion.
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  1. Some common drug-metabolizing reactions have been demonstrated in sheep rumen, abomasum, duodenum, jejunum, ileum and colon.
- 2.
  2. Reactions studied were: epoxidation, O- and N-demethylation, hydroxylation, azo- and nitro-reduction, glucuronidation, N-acylation, N-deacetylation, hydrolysis and glutathione conjugation. Cytochrome P-450 and cytochrome b₅ were also measured.
- 3.
  3. Generally speaking, in all regions of the gastrointestinal tract examined, the majority of the reactions studied had measurable activity. Biphenyl hydroxylase and glycine N-acylase activities were too low to measure accurately.

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Research ArticlesIntestinal Drug Absorption and Metabolism III: Glycine Conjugation and Accumulation of Benzoic Acid in Rat Intestinal Tissue

Abstract

Biochem. Pharmacol.

J. Pharm. Sci.

J. Biol. Chem.

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J. Pharm. Sci.

Int. Rev. Cytol.

Research Articles
Intestinal Drug Absorption and Metabolism III: Glycine Conjugation and Accumulation of Benzoic Acid in Rat Intestinal Tissue