Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well known that during diarrhea episodes decreased cyclosporine and tacrolimus levels are often observed, usually requiring an increase in dose. An increase in tacrolimus trough levels is infrequently recognized as a potential cause of the adverse effect of severe diarrhea. Herein, we report the case of a renal transplant patient who displayed increased tacrolimus trough levels during an episode of gastroenteritis with severe diarrhea. The patient is 32-year-old male who received a renal transplant from his mother. Immunosuppression was initiated with tacrolimus in combination with mycophenolate mofetil and prednisone. The postoperative course was uneventful. The function of the transplanted kidney was normal. Eight months after transplantation he presented to our hospital with a history of high fever, abdominal pain, nausea and severe diarrhea. He was admitted with a diagnosis of enterocolitis of unknown etiology. The blood trough level of tacrolimus had increased from 6.7 ng/mL to 28.7 ng/mL after the onset of diarrhea. A therapeutic trough level of tacrolimus was reached 6 weeks after complete relief of diarrhea. Tacrolimus shows large variability in bioavailability after oral administration, both due to intestinal metabolism by cytochrome P450 (CYP3A4) and active secretion from enterocyte into intestinal lumen by P-glycoprotein. The epithelial cells of the intestine, may be destroyed abrogating P-glycoproteins during the course of enterocolitis, thereby increasing the levels of tacrolimus. It is recommended to monitor trough levels of tacrolimus during severe diarrhea of any nature to prevent tacrolimus-related complications.
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PMID:Increased tacrolimus trough levels in association with severe diarrhea, a case report. 1551 58

Recent studies suggest that P-glycoprotein (Pgp) encoded by MDR1 gene, may be an important factor in the pathogenesis of inflammatory bowel disease (IBD). In this study, we investigated intestinal Pgp expression and activity: (1) in IL10 deficient (IL10(-/-)) mice which spontaneously develop intestinal inflammation affecting the small and large intestine and (2) in DSS (dextran sodium sulfate)-induced rat colitis. In IL10(-/-) enterocolitis mice, rhodamine 123 efflux was reduced by two to three-fold along the small and large intestine. This decrease was associated with a reduction in membrane's Pgp protein levels. A similar three-fold decrease in Pgps activity and expression was observed in the proximal colon in DSS-induced colitis in rats. However, in the non-inflamed ileum in DSS-induced rat colitis, epithelial cell's Pgp activity and protein levels were unexpectedly increased. This effect was specific to local inflammation since LPS induced systemic inflammation did affect neither the intestinal rho 123 efflux transport nor the abundance of the Pgp protein. These data demonstrate for the first time, an impaired function of epithelial Pgp in IL10 deficient enterocolitis mice. They also show an increase in Pgps activity in the non-inflamed ileum in the DSS-induced rat colitis, which may represent an adaptive mechanism to compensate the impaired activity of Pgp in the colon.
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PMID:Intestinal inflammation induces adaptation of P-glycoprotein expression and activity. 1588 61