| Enhancement of the oral bioavailability of phenytoin by N-acetylation and absorptive characteristics. | |
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MedLine Citation:
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PMID: 9821815 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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To improve the absorbability of phenytoin (DPH), a prodrug, N-acetyl-DPH (EDPH), was synthesized, and the absorptive characteristics and pharmacokinetics of the prodrug were evaluated in rats. EDPH was rapidly hydrolyzed to DPH in the intestinal fluid and the mucosa (rate constant, 0.055 and 0.169 min(-1), respectively). The plasma concentrations of DPH after intravenous dosing of EDPH declined in a biexponential manner, although two different elimination patterns were observed in these rats. When dosed orally (25 mg/kg, DPH equivalent), the plasma levels of DPH converted from the prodrug were significantly higher and more sustained than those after DPH alone, giving bioavailability 11.4 (rapid decay) and 9.1 times (slow decay) as high, respectively, as that after DPH alone. The concentrations of DPH distributed into the mucosa of the duodenum and jejunum 1 and 5 h after oral dosing of EDPH were significantly higher than those after DPH alone. The prodrug and DPH converted from the prodrug dissolved 2-4 fold more than DPH alone in bile salt solution and bile salt-oleic acid mixed micelles, indicating the increased solubility of the prodrug in the intestinal fluid. It is concluded from the data that such high solubility of EDPH enhanced the intestinal absorption of the prodrug, part of which would be absorbed in the amide form, and thus gave the high bioavailability. |
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Authors:
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T Ogiso; T Tanino; D Kawaratani; M Iwaki; G Tanabe; O Muraoka |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biological & pharmaceutical bulletin Volume: 21 ISSN: 0918-6158 ISO Abbreviation: Biol. Pharm. Bull. Publication Date: 1998 Oct |
Date Detail:
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Created Date: 1999-01-14 Completed Date: 1999-01-14 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9311984 Medline TA: Biol Pharm Bull Country: JAPAN |
Other Details:
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Languages: eng Pagination: 1084-9 Citation Subset: IM |
Affiliation:
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Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Administration, Oral Animals Bile Acids and Salts / chemistry Biological Availability Buffers Hydrolysis Intestinal Absorption Intestinal Mucosa / metabolism Liver / metabolism Male Micelles Phenytoin / analogs & derivatives*, blood, chemical synthesis, chemistry, pharmacokinetics*, pharmacology Prodrugs / chemical synthesis, pharmacokinetics* Rats Rats, Wistar Solubility Tissue Distribution Water / chemistry |
| Chemical | |
Reg. No./Substance:
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0/Bile Acids and Salts; 0/Buffers; 0/Micelles; 0/N-acetylphenytoin; 0/Prodrugs; 56775-94-1/1-acetyl-3-acetoxy-5',5-diphenylhydantoin; 57-41-0/Phenytoin; 7732-18-5/Water |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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