Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.6.3.44 (
P-glycoprotein
)
13,344
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
P-glycoprotein
170 encoded by the MDR-1 gene mediates export of substrates including some immunosuppressive drugs. Rapamycin was compared to cyclosporine A for its ability to inhibit
P-glycoprotein
on normal human peripheral blood mononuclear cells (PBMC). Rhodamine 123 dye efflux measures
P-glycoprotein
activity and inhibition of
P-glycoprotein
results in dye retention. Normal CD4+, CD8+ and B cells include a substantial subset with cyclosporine A-sensitive rhodamine efflux. Rh123 dye efflux is also inhibited by rapamycin at comparable drug levels used in transplant models. CsA is approximately 100-fold more effective on inhibition of PBMC P-gp than is
RAPA
.
P-glycoprotein
inhibition of ex vivo lymphocytes with three multi-drug resistant T-cell lines showed susceptibility of
P-glycoprotein
to rapamycin dependent on the cell type. Compared to cyclosporine A, the reduced ability of rapamycin to inhibit
P-glycoprotein
reflects a reduced avidity in its binding to
P-glycoprotein
and perhaps increased access to the cell interior. The increased efficiency of
RAPA
as an immunosuppressive may in part be a result of its relatively low avidity for
P-glycoprotein
. The authors speculate that interactions with
P-glycoprotein
may partially modulate the immunosuppressive effects of rapamycin.
...
PMID:Inhibition by rapamycin of P-glycoprotein 170-mediated export from normal lymphocytes. 866 25
Sirolimus (rapamycin, RAPAMUNE,
RAPA
) is an immunosuppressive agent used for the prophylaxis of renal allograft rejection and exhibits an immunosuppressive mechanism that is distinct from that for cyclosporine and tacrolimus. The purpose of this manuscript is to discuss the exposure-response relationships and drug interactions of sirolimus. The various factors affecting sirolimus whole blood exposure included first-pass extraction, formulation, food, demographics, liver disease, assay method, and interacting drugs. Clinically significant effects caused by food, pediatric age, hepatic impairment, and interacting drugs require recommendations for the safe and efficacious use of sirolimus in renal allograft patients. An exposure-response model based on multivariate logistic regression was developed using the interstudy data from 1832 renal allograft patients. The analysis revealed an increased probability of acute rejection for sirolimus troughs <5 ng/mL, cyclosporine troughs <150 ng/mL, human leukocyte antigen (HLA) mismatches > or =4, and females. The outcomes suggested that individualization of sirolimus doses immediately after transplantation, based on HLA mismatch and sex, would likely decrease the probability of acute rejections in renal allograft recipients who receive concomitant sirolimus, cyclosporine (full-dose), and corticosteroid therapy. Sirolimus is a substrate for both Cytochrome P450 3A (CYP3A) and
P-glycoprotein
(
P-gp
) and undergoes extensive first-pass extraction. Drugs that are known to inhibit or induce these proteins may potentially affect sirolimus whole blood exposure. In healthy volunteers, cyclosporine, diltiazem, erythromycin, ketoconazole, and verapamil significantly increased sirolimus whole blood exposure, and rifampin significantly decreased sirolimus exposure. However, sirolimus whole blood exposure was not affected by acyclovir, atorvastatin, digoxin, ethinyl estradiol/norgestrel, glyburide, nifedipine, or tacrolimus. Among the 15 drugs studied, sirolimus significantly increased the exposures of only erythromycin and S-(-)verapamil.
...
PMID:Exposure-response relationships and drug interactions of sirolimus. 1576 93
