In vitro inhibition of midazolam and quinidine metabolism by flavonoids.

ABSTRACT

Studies in humans in vivo have demonstrated that substances found in grapefruit juice may increase the bioavailability of dihydropyridine derivatives as a result of the inhibition of liver enzyme activities by flavonoids found in grapefruit. Since the metabolism of dihydropyridine drugs is mediated by cytochrome P-450 (CYP) 3A4, it has been hypothesized that flavonoids may also influence the metabolism of other drugs, such as midazolam and quinidine, which are biotransformed by the same CYP isoform. Three flavonoids, kaempferol, naringenin and quercetin, are found in grapefruit juice but not in orange juice. The effect of these substances on the metabolism of midazolam and quinidine has been investigated in human liver microsomes. In the concentration range 10-160 microM the inhibitory potential of flavonoids was the same for both of the tested drugs; it decreased in the order quercetin >> kaempferol > naringenin. The data suggest that the flavonoids found in grapefruit juice may influence the kinetics of midazolam and quinidine in man.