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Cyclosporin metabolism by human gastrointestinal mucosal microsomes
I R Webber1, W H Peters, D J Back
1Department of Pharmacology and Therapeutics, University of Liverpool.
Abstract:
The in vitro metabolism of the immunosuppressant cyclosporin (CsA) by human gastrointestinal mucosal microsomes has been studied. Macroscopically normal intestinal (n = 4) and liver (n = 2) tissue was obtained from kidney transplant donors, and microsomes prepared. Intestinal metabolism was most extensive with duodenal protein (15% conversion to metabolites M1/M17 after 2 h incubation at 37 degrees C; metabolite measurement by h.p.l.c). Western blotting confirmed the presence of P-4503A (enzyme subfamily responsible for CsA metabolism) in duodenum and ileum tissue, but not in colon tissue. The results of this study indicate that the gut wall may play a role in the first-pass metabolism of CsA, and could therefore be a contributory factor to the highly variable oral bioavailability of CsA.
Insights
Human gastrointestinal mucosal microsomes metabolize the immunosuppressant cyclosporin (CsA). The gut wall contributes to CsA
Area of Science:
- Pharmacology
- Drug Metabolism
- Gastroenterology
Background:
- Cyclosporin (CsA) is a vital immunosuppressant.
- Its oral bioavailability is highly variable.
- Understanding CsA metabolism is crucial.
Purpose of the Study:
- To investigate the in vitro metabolism of CsA by human gastrointestinal mucosal microsomes.
- To determine the role of the gut wall in CsA first-pass metabolism.
Main Methods:
- Human intestinal and liver tissues obtained from kidney transplant donors.
- Microsomal preparation and incubation.
- High-performance liquid chromatography (h.p.l.c.) for metabolite analysis.
- Western blotting to detect cytochrome P450 3A (CYP3A).
Main Results:
- Intestinal metabolism of CsA was observed, particularly in the duodenum.
- Significant conversion of CsA to metabolites M1/M17 occurred.
- Cytochrome P450 3A, responsible for CsA metabolism, was present in the duodenum and ileum, but not the colon.
- Liver microsomes also showed CsA metabolism.
Conclusions:
- The gut wall plays a significant role in the first-pass metabolism of CsA.
- This intestinal metabolism may contribute to the observed variability in CsA oral bioavailability.
- Further research into gut wall metabolism is warranted.