Source:http://linkedlifedata.com/resource/pubmed/id/15285845
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
8
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pubmed:dateCreated |
2004-8-2
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pubmed:abstractText |
Grapefruit juice can modify the pharmacokinetic parameters of many drugs, in particular simvastatin, an orally active cholesterol-lowering agent. The exact components in grapefruit juice responsible for drug interactions are not perfectly known. However, it seems that bergamottin, a furocoumarin derivative, is one of the main active components within grapefruit juice. The objective of this paper was to quantify and to characterize in-vitro the inhibitory effect of bergamottin on simvastatin metabolism by using rat and human liver microsomes. In rat liver microsomes, the incubation conditions (+/-NADPH) of bergamottin were found to influence its inhibiting capacity. In co-incubation with simvastatin, the Ki value (the equilibrium dissociation constant for the enzyme-inhibitor complex) was higher (Ki = 174 +/- 36 microM) than in pre-incubation (Ki = 45 +/- 6 microM and 4 +/- 2 microM, without and with NADPH, respectively). It thus seems that the pre-incubation of bergamottin (in particular with NADPH) increases its inhibiting capacity on simvastatin metabolism. Bergamottin metabolism study in rat liver microsomes showed the formation of two metabolites that were CYP-450 dependent. In contrast, in human liver microsomes, the incubation conditions of bergamottin did not influence its inhibiting capacity of simvastatin metabolism (Ki = 34 +/- 5 microM, Ki = 22 +/- 5 microM, Ki = 27 +/- 11 microM in coincubation and pre-incubation without and with NADPH, respectively). In rat and man, bergamottin was found to be a mixed-type inhibitor of simvastatin hepatic metabolism. However, in rat, bergamottin was partially a mechanism-based inhibitor by involvement of either bergamottin alone or one of its metabolites. The results highlight the importance of validating in-vitro models to help verify the suitability of the in-vitro model for predicting the nature and degree of metabolic drug interactions.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-3573
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
56
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1007-14
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pubmed:meshHeading |
pubmed-meshheading:15285845-Animals,
pubmed-meshheading:15285845-Anticholesteremic Agents,
pubmed-meshheading:15285845-Beverages,
pubmed-meshheading:15285845-Cells, Cultured,
pubmed-meshheading:15285845-Chromatography, High Pressure Liquid,
pubmed-meshheading:15285845-Citrus paradisi,
pubmed-meshheading:15285845-Humans,
pubmed-meshheading:15285845-Male,
pubmed-meshheading:15285845-Psoralens,
pubmed-meshheading:15285845-Rats,
pubmed-meshheading:15285845-Rats, Wistar,
pubmed-meshheading:15285845-Simvastatin
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pubmed:year |
2004
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pubmed:articleTitle |
Inhibition of in-vitro simvastatin metabolism in rat liver microsomes by bergamottin, a component of grapefruit juice.
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pubmed:affiliation |
UMR CNRS 7034, Faculté de Pharmacie, Université Louis Pasteur, Strasbourg, France.
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pubmed:publicationType |
Journal Article
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