Effects of Clarithromycin and Ketoconazole on FK506 Metabolism in Different CYP3A4 Genotype Recombinant Metabolic Enzyme Systems
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Current drug metabolism - (2024) vom: 20. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wen, Jinhua [VerfasserIn] |
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| Links: |
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| Themen: |
CYP3A4 |
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| Anmerkungen: |
Date Revised 25.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.2174/0113892002286019240315052145 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370131045 |
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| 245 | 1 | 0 | |a Effects of Clarithromycin and Ketoconazole on FK506 Metabolism in Different CYP3A4 Genotype Recombinant Metabolic Enzyme Systems |
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| 500 | |a Date Revised 25.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a CYP3A4*18B. | |
| 650 | 4 | |a CYP3A4*1B | |
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| 650 | 4 | |a ketoconazole | |
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| 700 | 1 | |a Yang, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Weiqiang |e verfasserin |4 aut | |
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