| Co-Investigator(Kenkyū-buntansha) |
TAKANAGA Hitomi Faculty of Pharmaceutical Sciences, KYUSHU UNIVERSITY,Assistant Professor, 薬学部, 助手 (20284523)
SHOYAMA Yukihiro Faculty of Pharmaceutical Sciences, KYUSHU UNIVERSITY,Professor, 薬学部, 教授 (70037604)
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| Budget Amount *help |
¥10,800,000 (Direct Cost: ¥10,800,000)
Fiscal Year 1998: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1997: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Research Abstract |
The simultaneous intake of grapefruit juice (GFJ) is known to alter the efficacies and pharmacokinetics of various drugs such as dihydropyridine calcium blockers, cyclosporin A and terfenadine. It has been reported that the mechanism of this interaction is proposed to be a supression of drug metabolism by cytochrome P450 3A4 (CYP3A4), which is responsible for the metabolism of these drugs. While, the striking overlap of substrates and inhibitors between CYP3A4 and P-glycoprotein (P-gp) was discussed and as a result, the effect of GFJ components on P-gp may thus be a factor to increase the bioavailabilities of drugs. So, we examined the effect of GFJ components on the absorption of drugs from digestive tracts.
We investigated the effect of GFJ and the different sections of grapefruit on the transport of vinblastine, a substrate of P-gp, across Caco-2 cells, a human colonic adenocarcinoma cell line, LLC-PKI cells, a porcine kidney epithelial cell line, and LLC-GA5-COL300 cells, LLC-PK1 ce
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lls transfected with human MDR1 cDNA.The steady-state uptake of [^<23>H]vinblastine ([^<23>H]VBL) from the apical side of Caco-2 cells was significantly increased in the presence of GFJ in a dose-dependent manner. However, the initial uptake of [3H]VIBL was not altered. So, it was suggested that the efflux of [^<23>H]VBL from Caco-2 cells by P-gp might be especially inhibited by GFJ.Moreover, the effect of the three different sections of grapefruit, such as the fresh grapefruit juice, the albedo and the peel, on the uptake of [^<23>H]VBL by Caco-2 cells was examined. The steady-state uptake of [^<23>H]VBL was increased in the presence of all parts of grapefruit. Simillary the effect of organic solvent extracts of GFJ and 6', 7'- dihydroxybergamottin (DHBG), we isolated in this study, on the uptake of [^<23>H]VBL by LLC- PK1 cells and LLC-GA5-COL300 cells. The uptake of [^<23>H]VBL by LLC-GA5-COL300 cells was low as compared with LLC-PK1 cells and it was increased in the presence of ethyl acetate extracts or 20muM DHLBG.Then, the effect of DHBG on the 6-beta hydroxylation of teststerone and the uptake of [^<23>H]VBL by Caco-2 cells were examined. The uptake of [^<23>H]VBL by Caco-2 cells was increased, while the 6-beta hydroxylation of teststerone was decreased in the presence of DHBG.It has already reported that DHIBG, we isolated in this study, was an inhibitor of CYP3A4 and the inhibitory effect of DHBG was due to the decrease of the amount of CYP3A4 in the digestive tracts. These results demonstrate that DHGB possess the inhibitory effects between on the drug metabolism and on the active efflux system. Less
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