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Metabolism of FK 506 in differentially induced rat liver microsomes
D D Stiff1, R Venkataramanan, T N Prasad
1Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pennsylvania 15261.
Abstract:
The in vitro hepatic metabolism of FK 506 was studied in microsomes prepared from control rats as well as in microsomes prepared from rats treated with the selective cytochrome P-450 isozyme inducers 3-methylcholanthrene (IA), phenobarbital (IIB), and dexamethasone (IIIA). The metabolism of FK 506 was similar for control microsomes and for microsomes prepared from phenobarbital and 3-methylcholanthrene induced animals. The percentage of FK 506 metabolized by these tissue preparations ranged from 21.7 to 32.7%. In contrast, the percentage of FK 506 metabolized by dexamethasone induced microsomes was 86.4%. The metabolism of FK 506 was not effected when the selective IA and IIB isozyme inhibitors alpha-naphthoflavone and orphenadrine were added to the incubations. However, the metabolism of FK 506 decreased by approximately 44% when the IIIA specific isozyme inhibitor troleandomycin was added to the dexamethasone induced microsomes. Therefore, the metabolism of FK 506 is apparently mediated primarily by the steroid inducible cytochrome P-450 IIIA isozyme.
Insights
The immunosuppressant FK 506 (tacrolimus) is primarily metabolized by the steroid-inducible cytochrome P-450 IIIA enzyme in rat liver microsomes. This specific enzyme pathway significantly enhances FK 506 breakdown.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Metabolism
Background:
- FK 506 (tacrolimus) is a crucial immunosuppressant drug.
- Understanding its metabolic pathways is vital for optimizing therapeutic use.
- Cytochrome P-450 (CYP) enzymes play a key role in drug metabolism.
Purpose of the Study:
- To investigate the in vitro hepatic metabolism of FK 506.
- To identify the specific cytochrome P-450 isozymes involved in FK 506 metabolism.
Main Methods:
- Incubation of FK 506 with rat liver microsomes from control and induced rats.
- Treatment of rats with specific CYP inducers: 3-methylcholanthrene (IA), phenobarbital (IIB), and dexamethasone (IIIA).
- Use of selective CYP isozyme inhibitors: alpha-naphthoflavone (IA), orphenadrine (IIB), and troleandomycin (IIIA).
Main Results:
- FK 506 metabolism was similar in control, CYP IA, and CYP IIB induced microsomes (21.7-32.7% metabolized).
- Dexamethasone (CYP IIIA) induced microsomes showed significantly higher FK 506 metabolism (86.4%).
- Troleandomycin, a CYP IIIA inhibitor, reduced FK 506 metabolism by approximately 44% in dexamethasone-induced microsomes.
Conclusions:
- The steroid-inducible cytochrome P-450 IIIA isozyme is primarily responsible for FK 506 hepatic metabolism in rats.
- This finding highlights the importance of CYP IIIA in FK 506 pharmacokinetics.
- Further research into CYP IIIA activity can inform FK 506 dosing and drug interaction studies.