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.
The prediction method for the plasma concentration-time profile of N-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.
Kimura
T
T
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan. kimura@pheasant.pharm.okayama-u.ac.jp
Iwasaki
N
N
Yokoe
J I
JI
Haruta
S
S
Yokoo
Y
Y
Ogawara
K I
KI
Higaki
K
K
D000284:Administration, Oral; D000316:Adrenergic alpha-Agonists / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000465:Algorithms; D000818:Animals; D001515:Beer / Q000032:analysis*; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism*; D008297:Male; D011169:Portal Vein / Q000502:physiology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D014439:Tyramine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
D000316:Adrenergic alpha-Agonists; D001798:Blood Proteins; D005755:Gastrins; C036244:methyl-4-tyramine; D014439:Tyramine