1992 Fiscal Year Final Research Report Summary
Studies on prodrugs utilizing the metabolism in the intestinal microorganisms
| Project/Area Number |
03671028
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | Nagasaki University |
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Principal Investigator |
NAKAMURA Junzo Nagasaki University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (30115901)
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| Project Period (FY) |
1991 – 1992
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| Keywords | microorganism / metabolism / prodrug / rabbit / absorption / salicylic acid / amino acid conjugate / enantiomer |
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| Research Abstract |
The significance of the intestinal microorganisms to pharmacokinetics and pharmacology has been emphasized with respect to their ability to metabolize drugs and foreign compounds. We demonstrated that glycine conjugate of salicylic acid was metabolized to salicylic acid by intestinal microorganisms in rabbits, rats and dogs. Furthermore, we examined the effect of fasting or pretreatment with antibiotics on the hydrolysis of salicyluric acid in rabbit intestinal microorganisms. Further study showed that oral treatment with salicylic acid caused severe damage in the rabbit gastric mucosa, but severe damage in the gastric mucosa was not found in rabbits treated with salicyluric acid, suggesting that prodrugs utilizing the metabolism in the intestinal microorganisms may be useful in reducing the gastrointestinal mucosal damage. The elucidation of the effect of amino acid or dipeptide moiety on the fate of salicylic acid is considered to offer a promising approach to develop an effective prodrug of salicylic acid. In the present study, we examined the fate of salicylic acid-L-alanine, -D-alanine, -L-glutamic acid, -L-methionine, -L-tyrosine and -glycylglycine conjugates following oral, intravenous, cecal and rectal administration in rabbits. The accumulation of systematic information on the pharmacokinetic properties of amino acid or dipeptide conjugates of salicylic acid would improve the design of a prodrug which can control the blood concentration and deliver to the large intestine.
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