Inhibition of in-vitro simvastatin metabolism in rat liver microsomes by bergamottin, a component of grapefruit juice.
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.
UMR CNRS 7034, Faculté de Pharmacie, Université Louis Pasteur, Strasbourg, France.
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Le Goff-Klein
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Klein
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Hérin
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JC
Koffel
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Ubeaud
D000818:Animals; D000924:Anticholesteremic Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001628:Beverages; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D032083:Citrus paradisi; D011564:Furocoumarins / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000924:Anticholesteremic Agents; D011564:Furocoumarins; D019821:Simvastatin; C068337:bergamottin