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Research ArticleArticle

Analysis and Prediction of Absorption Profile Including Hepatic First-Pass Metabolism of N-Methyltyramine, A Potent Stimulant of Gastrin Release Present in Beer, after Oral Ingestion in Rats by Gastrointestinal-Transit-Absorption Model

Toshikiro Kimura, Norio Iwasaki, Jun-Ichi Yokoe, Shunji Haruta, Yoshiaki Yokoo, Ken-Ichi Ogawara and Kazutaka Higaki
Drug Metabolism and Disposition May 2000, 28 (5) 577-581;
Toshikiro Kimura
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Norio Iwasaki
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Jun-Ichi Yokoe
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Shunji Haruta
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Yoshiaki Yokoo
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Ken-Ichi Ogawara
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Kazutaka Higaki
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Abstract

The prediction method for the plasma concentration-time profile ofN-methyltyramine (NMT), a potent stimulant of gastrin release present in beer after oral ingestion in rats was examined using the previously developed Gastrointestinal (GI)-Transit-Absorption Model, with the addition of a process of hepatic first-pass metabolism. Phenol red was used as a nonabsorbable marker for estimation of the GI transit rate constant for eight segments in the GI tract. The first order absorption rate constant for each segment was estimated by means of a conventional in situ closed loop method. The results of in situ absorption experiments showed that NMT is well absorbed in the small intestine, especially in the duodenum and jejunum. Using the GI-Transit-Absorption Model, it was demonstrated that more than 90% of orally ingested NMT is absorbed in the small intestine, and that the substantial absorption site for NMT in vivo is the lower jejunum and the ileum. However, the observed bioavailability was only 39.0%. The in vitro metabolism study clarified that NMT is metabolized in the liver, but not in the small-intestinal mucosa. With the hepatic intrinsic clearance value (2.0 liters/h) calculated from the rate of metabolism in vitro, the hepatic availability was estimated to be 0.510 on the basis of a well stirred model, which was validated by two other methods to calculate the hepatic availability of NMT. The plasma concentration-time curve and bioavailability of NMT after oral ingestion were well predicted by the GI-Transit-Absorption Model with the hepatic first-pass metabolism process.

Footnotes

  • Send reprint requests to: Prof. Toshikiro Kimura, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan. E-mail: kimura{at}pheasant.pharm.okayama-u.ac.jp

  • Abbreviations used are::
    GI
    gastrointestinal
    NMT
    N-methyltyramine
    ki
    transit rate constant
    kai
    absorption rate constant
    Fa
    fraction absorbed
    AUCra
    area under the absorption rate-time curve
    CLint,h
    hepatic intrinsic clearance
    Fh
    hepatic availability
    Qh
    hepatic (portal) blood flow
    fp
    unbound fraction in plasma
    RB
    blood-to-plasma concentration ratio
    • Received September 20, 1999.
    • Accepted January 14, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (5)
Drug Metabolism and Disposition
Vol. 28, Issue 5
1 May 2000
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Research ArticleArticle

Analysis and Prediction of Absorption Profile Including Hepatic First-Pass Metabolism of N-Methyltyramine, A Potent Stimulant of Gastrin Release Present in Beer, after Oral Ingestion in Rats by Gastrointestinal-Transit-Absorption Model

Toshikiro Kimura, Norio Iwasaki, Jun-Ichi Yokoe, Shunji Haruta, Yoshiaki Yokoo, Ken-Ichi Ogawara and Kazutaka Higaki
Drug Metabolism and Disposition May 1, 2000, 28 (5) 577-581;

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Research ArticleArticle

Analysis and Prediction of Absorption Profile Including Hepatic First-Pass Metabolism of N-Methyltyramine, A Potent Stimulant of Gastrin Release Present in Beer, after Oral Ingestion in Rats by Gastrointestinal-Transit-Absorption Model

Toshikiro Kimura, Norio Iwasaki, Jun-Ichi Yokoe, Shunji Haruta, Yoshiaki Yokoo, Ken-Ichi Ogawara and Kazutaka Higaki
Drug Metabolism and Disposition May 1, 2000, 28 (5) 577-581;
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