2003 Fiscal Year Final Research Report Summary
Study of medication design considering the drug metabolic activities in neonatal period.
| Project/Area Number |
14370779
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Chiba University |
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Principal Investigator |
KITADA Mitsukazu Chiba University, University Hospital, Professor, 医学部附属病院, 教授 (90110345)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Itsuko Chiba University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究院, 助教授 (00202929)
ARIYOSHI Noritaka Chiba University, University Hospital, Associate Professor, 医学部附属病院, 助教授 (00243957)
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| Project Period (FY) |
2002 – 2003
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| Keywords | neonate / drug metabolism / CYP3A4 / CYP3A7 / endogenous steroids / urinary 6β-OHF / C ratio |
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| Research Abstract |
1.The CYP3A7-mediated drug and endogenous steroid metabolic activities were lower than those of CYP3A4 except DHEA and DHEA-S 16α-hydroxylation. The difference in the activities between CYP3A4 and CYP3A7 was dependent on the substrate used. The results obtained from site-directed-mutagenesis enzymes suggested that the position of Lis-224 and Lis-244 are important for CYP3A7 substrate specificities.
2.CYP3A7 mediated CBZ 10,11-epoxidation and NVP 2-, 12-hydroxylation were activated by sulfate conjugated steroids, although CYP3A4 mediated these reactions were not affected. Especially, DHEA-S was found to be a potent activator for these drug metabolism. From the fact that DHEA-S and CYP3A7 exist at very high levels In the neonatal period, it is likely to assume that DHEA-S may affect drug metabolism In this period. Furthermore, from the results of theoretical calculation, it is strongly suggested that the change in the activity of CYP3A may be attributable to interaction substrate and endogenous steroid in the active site of the enzyme.
3.Urinary 6β-OHF/C ratio and 16α-hydroxyDHEA/CRE ratio were measured after birth in human neonates as marker of CYP3A and CYP3A7 activities, respectively. Both ratios decreased day by day to one week after birth. And after one week, the urinary 6β-OHF/C ratio shifted to the increase while the 16α-hydroxyDHEA/CRE ratio continued gradual decrease. These results indicate that the CYP3A7 level decrease gradually after birth, and the CYP3A4 level gradually increase about one week after birth.
In conclusion, the quantitative and/or qualitative changes in the forms of CYP3A enzymes occur at the neonatal period, and the substrate specificities and effects of endogenous steroids were different between CYP3A7 and CYP3A4.
Consequently, it is considered that changes in the drug metabolic activities during neonatal period may be dependent on the kind of medicine.
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