1998 Fiscal Year Final Research Report Summary
Pharmacokinetic Evaluation of First-Pass Effect of Enantiomer
| Project/Area Number |
09672187
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
YAMAOKA Kiyoshi Graduate School of Pharmaceu-Science, Kyoto University Associate Professor, 薬学研究科, 助教授 (50109013)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Enantiomorph / Intestinal Metabolism / First-Pass Effect / Method of PS-DD / Hepatic Disposition / Intestinal Absorption / Systemic Disposition |
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| Research Abstract |
Semotiadil and levosemotiadil which are R- and S-enantiomers, respectively, show different physiological activity and pharmacokinetics. By a perfusion experiment the hepatic recovery ratios, FH, of semotiadil and levosemotiadil were 2% and 10%, respectively, which demonstrates that R-enantiomer was extensively eliminated though the rat liver. The mean transit time tH of semotiadil and levosemotiadil were 0.15min and 0.20min, respectively, which were statistically different. The extent of distribution of S-isomer was significantly greater than that of R-isomer. 5'-deoxy-5-fluorouridine (DFUR) is a prodrug of 5'-fluorouracil(5-FU). 5-FU is generated from DFUR in the intestinal wall. Therefore, these two drugs are adopted as a drug model pair for the intestinal metabolism. When DFUR was administered orally to a conscious rat, 65% of DFUR administered as intact form and 7% of DFUR was found as 5-FU in the portal vein. The mean absorption times of these two drugs were almost the same, which means that 5-FU generated from DFUR was further extensively eliminated in the intestinal wall. Another experiment by coadministration of DFUR and uridine demonstrates that uridine inhibited extensively the degradation of 5-FU generated from DFUR.BOF-4272 is the racemic mixture which consists of R- and D-enantiomers. In perfusion experiments at 37oC and 4oC by changing the perfusate BSA concentration, R-isomer is more extensively eliminated than S-isomer in the present of BSA and at 37oC.The extent of elimination was the same between R- and S-isomer in the absence of perfusate BSA or at 4oC, The experiment at 4oC demonstrated that there is a equilibrium distribution phase which is difficult to be observed at 37oC.The efficient hepatic elimination of BOF-4272 was explained by this equilibrium distribution phase.
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