1992 Fiscal Year Final Research Report Summary
Molecular mechanism of non-linear first-pass metabolism
| Project/Area Number |
03671043
|
|---|
| Research Category |
Grant-in-Aid for General Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Biological pharmacy
|
|---|
| Research Institution | Chiba University |
|---|
Principal Investigator |
SUZUKI Tokuji Chiba Univ., Dept.Biopharm., Prof., 薬学部, 教授 (40010219)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MASUBUCHI Yasuhiro Chiba Univ., Dept.Biopharm., Res.Assoc., 薬学部, 助手 (10209455)
NARIMATSU Shizuo Chiba Univ., Dept.Biopharm., Assoc.Prof., 薬学部, 助教授 (20113037)
|
|---|
| Project Period (FY) |
1991 – 1992
|
| Keywords | non-linear first-pass metabolism / propranolol / bunitrolol / debrisoquine / Dark Agouti rat / P450BTL / genetic polymorphism / membrane transport |
|---|
| Research Abstract |
The results described below are obtained for the molecular basis of first-pass effects using various techniques such as pharmaco- kinetics, enzyme kinetics, drug metabolism and molecular enzymology.
1. Involvement of high-affinity cytochrome P-450 isozymes in non- linear first-pass metabolism of drugs. The high-affinity P-450 isozymes which are defect in Dark Agouti strain rats were shown to be involved in the non-linear first-pass metabolism of propranolol (PL) and bunitrolol (BTL).
2. Purification of cytochrome P450 isozymes. A P450 isozyme (P450BTL) belonging to the CYP2D subfamily was purified from liver microsomes of Sprague-Dawley rats by pursuing the oxidation activity of BTL. Reconstitution and immunochemical studies indicated that this isozyme played major roles in hydroxylations of debrisoquine, BTL and PL in rat liver microsomes.
3. Mechanisms of first-pass effects of beta-blockers. In the isolated rat liver perfusion system, outflow PL concentrations were non-linearly increased against inflow PL concentrations. The metabolic rates observed in this system were predicted using the microsomal kinetic parameters, indicating the non-linear PL first-pass metabolism is due to the saturation of the reactions for the high-affinity enzymes engaging in PL ring hydroxylations.The mechanisms causing a difference between bioavailabilities of PL and BTL were studied in Wistar rats by the multiple indicator dilution technique. Kinetic analysis of the data obtained suggested that a difference not only in metabolic clearance but also in permeation clearance of each drug through cell membranes caused the difference between their bioavailabilities.
|
