Remark : Within 0.1 to 10 micrograms/mL, the hydrolyzed ginkgolides showed direct inhibition against CYP1A2, 2B6,2C8,2C9,2C19,2D6,2E1,3A4m (midazolam as substrate) and 3A4t (testosterone as sustrate), with IC50 values determined to be 410 micrograms/mL (concentrations expressed as the sum of equivalent concentrations of ginkgolideA, B and K). For the metabolism-dependent inhibition studies, the preincubation of 30 min did not substantially alter the IC50 values when compared with the corresponding values in the direct inhibition studies. The activities and mRNA expression levels for CYP1A2 and 2B6 with in each drug-treated group (0.1, 1 and 10 micrograms/mL) were not affected after the 48-h incubation. For CYP3A4, the activity and mRNA expression level were not altered when incubated with 0.1 and 1 micrograms/mL of hydrolyzed ginkgolides. When incubated with hydrolyzed ginkgolides at 10 micrograms/mL, the relative activity and relative mRNA expression level of CYP3A4 remarkably increased to 4.59+/-3.67 and 17.2+/-9.16-fold of corresponding vehicle control values, respectively. The hydrolyzed ginkbolides is not likely to cause DDI via inhibition of the major human CYPs.
