[Effect of ketoconazole on the activity of CYP4503A4 and CYP450 1A2 of hepatic microsomes in healthy adults].

OBJECTIVE: To observe the effect of ketoconazole on the activity of cytochrome P450 (CYP) 1A2 and 3A4 in hepatic microsomes of healthy adults.

METHODS: Human hepatic microsomes obtained from healthy adults were randomly divided into control group and ketoconazole-treatment groups at different concentrations. After 15 min of culture, the substrates (testosterone for CYP3A4 and phenacetin for CYP1A2) were added and incubated for another 20 min. The metabolites (6-testosterone and acetaminophen) were then measured with high-performance liquid chromatography (HPLC) to assess the activities of CYP3A4 and 1A2.

RESULTS: Significant difference was found between the groups in the quantity of 6-testosterone and the relative activity of CYP3A4 (P<0.05). The IC(50) of ketoconazole for CYP3A4 was 0. 16 mg/L. Both the quantity of 6-testosterone and the relative activity of CYP3A4 were reduced gradually with the increment of ketoconazole concentration. Significant differences were found between the ketoconazole groups and the control group in both the quantity of acetaminophen and the relative activity of CYP1A2 (P<0.05). Ketoconazole at low doses reduced CYP1A2 activity and but increased the activities at high doses (P<0.05).

CONCLUSION: In the range of maximum clinical blood concentration, ketoconazole can inhibit the activity of CYP3A4, but not that of CYP1A2, in the hepatic microsomes in healthy adults.