2003 Fiscal Year Final Research Report Summary
In vivo functional characterization of the ABC transporters based on the genetic polymorphisms
| Project/Area Number |
13357020
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Tottori University |
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Principal Investigator |
IEIRI Ichiro Tottori University Hospital, Department of Hospital Pharmacy, Associate Professor, Vice Director, 医学部附属病院, 助教授 (60253473)
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| Co-Investigator(Kenkyū-buntansha) |
URAE Akinori Kyusyu Pharmacology Research Clinical, Director, 臨床研究部長
HIGUCHI Shun Kyusyu University, Faculty of Pharmaceutical Sciences, Professor, 大学院・薬学研究院, 教授 (40218699)
OTSUBO Kenji Tottori University Hospital, Department of Hospital Pharmacy, Professor, Director, 医学部附属病院, 教授 (80260701)
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| Project Period (FY) |
2001 – 2003
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| Keywords | ABC transporters / P-glycoprotein / MDR1 / BCRP / Basic research / Clinical Study |
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| Research Abstract |
Among the ABC transporters, we examined structural and functional characterizations of the two transporter genes, MDR1 and BCRP, from the 2 perspectives including basic and clinical study. In the basic study, we bat analyzed SNPs, which located in the coding region, and 5' and 3' untranslated regions, and then evaluated contributions to mRNA and/or protein expressions using human materials such as blood and full tern placentas. In the clinical study, we conducted following 4 clinical examinations ; (i)role of human MDR1 gene polymorphisms in bioavailability and interaction (with typical inhibiter, clarithromycin) profile of digoxin, a substrate of P-glycoprotein (PGP), in genotyping matched healthy volunteers ; (ii)Neurotoxicity (e-g.,epilepsy) induced by tacrolimus (a substrate of PGP) after liver transplantation : relation to genetic polymorphisms of the MDR1 gene ; (iii)Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine (a substrate of PGP) therapy ; (iv)role of human BCRP gene polymorphisms in the pharmacokinetic profiles of 4-methyl umbelliferone and its conjugated metabolites in healthy subjects.
Following observations could be obtained (only clinical consequences due to explanation space)
(1)Absorption from the gastrointestinal tracts (ie, bioavailability) and interaction profiles of PGP substrates seem to be influenced by polymorphisms in th. MDR1 gene.
(2)Brain penetration from blood of certain drugs may also be regulated by P-glycoprotein.
Based on these observations, we concluded that genetic polymorphism in the MDR1 is useful to the individual pharmacotherapy.
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