Title:Effects of Clarithromycin and Ketoconazole on FK506 Metabolism in Different
CYP3A4 Genotype Recombinant Metabolic Enzyme Systems
Volume: 25
Issue: 2
Author(s): Jinhua Wen*, Yuwei Xiao, Menghua Zhao, Chen Yang and Weiqiang Hu
Affiliation:
- The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
Keywords:
Clarithromycin, CYP3A4, tacrolimus, ketoconazole, CYP3A4*1B, CYP3A4*18B.
Abstract:
Objective: This study aimed to investigate the effects of clarithromycin and ketoconazole on the
pharmacokinetic properties of tacrolimus in different CYP3A4 genotype recombinant metabolic enzyme systems,
so as to understand the drug interactions and their mechanisms further.
Method: The experiment was divided into three groups: a blank control group, CYP3A4*1 group and
CYP3A4*18 recombinant enzyme group. Each group was added with tacrolimus (FK506) of a series of concentrations.
Then 1 umol/L clarithromycin or ketoconazole was added to the recombinant enzyme group and
incubated in the NADPH system for 30 minutes to examine the effects of clarithromycin and ketoconazole on
the metabolizing enzymes’ activity of different genotypes. The remaining concentration of FK506 in the reaction
system was determined using UPLC-MS/MS, and the enzyme kinetic parameters were calculated using
the software.
Results: The metabolism of CYP3A4*18 to FK506 was greater than that of CyP3А4*1B. Compared with the
CYP3A4*1 group, the metabolic rate and clearance of FK506 in the CYP3A4*18 group significantly increased,
with Km decreasing. Clarithromycin and ketoconazole inhibit the metabolism of FK506 by affecting
the enzyme activity of CYP3A4*1B and CYP3A4*18B. After adding clarithromycin or ketoconazole, the
metabolic rate of FK506 significantly decreased in CYP3A4*1 and CYP3A4*18, with Km increasing, Vmax
and Clint decreasing.
Conclusion: Compared with CYP3A4*1, CYP3A4*18 has a greater metabolism of FK506, clarithromycin
and ketoconazole can inhibit both the enzymatic activities of CYP3A4*1 and CYP3A4*18, consequently affecting
the metabolism of FK506 and the inhibitory on CYP3A4*1 is stronger.
