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

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By sequestering cytosolic calcineurin into a molecular complex with cyclophilin and its consequent T-cell dysfunction, some cyclosporins, such as CsA and FR901459 ([Thr2-Leu5-Leu10]-CsA), display potent immunosuppressive activity. Independently on this property, cyclosporins may display one or more other biological activities mediated by interaction with cell surface glycoproteins. Several cyclosporins inhibit the function of human MDRI-encoded P-glycoprotein (Pgp), a flippase known to cause cancer multidrug resistance, but also expressed by some normal immunocompetent cells and by normal epithelial cells which control drug bioavailability in vivo. CsA is known to be a potent Pgp inhibitor with a 3.2 microM IC50 in an assay where the most potent derivative SDZ PSC 833 gives a 0.49 microM IC50. FR901459 is now shown to be a good Pgp inhibitor, being 2-fold weaker only (IC50 of 6 microM) than CsA. Some cyclosporins may also inhibit the function of the human FPR1-encoded formyl peptide receptor (FPR), a chemotactic receptor whose absence is known to impair antibacterial immunity. Yet this inhibition is very weak for all, but one of them, CsH, whose 0.15 micro/M IC50 makes it a much more potent FPR inhibitor than CsA (IC50 >10 microM in the same assay). FR901459 is now shown to be a very potent inhibitor of FPR function (IC50 of 0.6 microM). Since CsH shows little Pgp-inhibitory activity and has no known immunosuppressive activity, FR901459 displays a unique pharmacological profile: like CsA, it inhibits T-cell function; less than CsA, it can inhibit Pgp function on selected leukocyte subsets and on epithelial barriers known to control drug bioavailability; however, much more efficiently than CsA, it can inhibit the FPR function, a receptor involved in some leukocytic inflammatory responses to chemotactic peptides.
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PMID:The potent immunosuppressive cyclosporin FR901459 inhibits the human P-glycoprotein and formyl peptide receptor functions. 1090 15

Cyclosporine and tacrolimus are substrates and potent inhibitors of the multidrug transporter, P-glycoprotein, in vitro. The authors have investigated the effect of chronic therapy with these and other immunosuppressive drugs on the expression and function of P-glycoprotein in T lymphocytes. Using a P-gp antibody, the authors studied the level of expression of P-gp in CD4 and CD8 T cells over a period of time in renal transplant patients. For comparison, a group of healthy volunteers and patients who did not receive any calcineurin inhibitors but were maintained on mycophenolate mofetil was included. The P-gp expression on lymphocytes from these two groups remained constant (over several months' time). However, patients who were started on tacrolimus or cyclosporine had an initial decline in expression of P-gp on CD4 T cells. Patients who were initiated on calcineurin therapy on day 1 posttransplant also had a decrease in expression of P-gp on CD4 T lymphocytes. This preliminary analysis suggests that the calcineurin inhibitors might be modulating the expression and function of transporters in lymphocytes, thus changing not only the drug concentration but also the apparent efficacy of these drugs. Further understanding and elucidation of such effects would be important in understanding the relationship between pharmacokinetics and pharmacodynamics of these and other drugs, especially for immunosuppressive and anti-AIDS therapy.
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PMID:Effect of calcineurin inhibitor therapy on P-gp expression and function in lymphocytes of renal transplant patients: a preliminary evaluation. 1186 67

The cytokine interleukin-17 may play a role in the recruitment of airway neutrophils, and interleukin-17 protein is increased in the airways of patients with asthma. In this study, we characterised the effect of interleukin-17 on the release of the neutrophil-recruiting cytokines granulocyte chemotactic protein (GCP)-2, growth-related oncogene (GRO)-alpha and interleukin-8 in human bronchial epithelial (HBE) cells. We also characterised the involvement of mitogen-activated protein (MAP) kinases as well as the effect of beta-adrenoceptor and glucocorticoid receptor stimulation and calcineurin and P-glycoprotein inhibition on these epithelial responses to interleukin-17. We found that interleukin-17 (1-1000 ng/ml) increased the release of GCP-2, GRO-alpha and interleukin-8 in a concentration-dependent manner. This interleukin-17-induced release of C-X-C chemokines was sensitive to inhibition of the p38 MAP kinase pathway and to stimulation of glucocorticoid receptors. In contrast, stimulation of beta-adrenoceptors increased the release of interleukin-8 and did not markedly alter the release of GCP-2 and GRO-alpha. Inhibition of calcineurin and of P-glycoproteins did not exert any substantial effect on the release of C-X-C chemokines. In conclusion, interleukin-17 bears the potential to increase neutrophil recruitment into the airways by releasing several, different C-X-C chemokines, including GCP-2, GRO-alpha and interleukin-8 in human bronchial epithelial cells. Inhibition of the p38 MAP kinase pathway and glucocorticoid receptor stimulation constitute two credible therapeutic strategies against this interleukin-17-induced release of neutrophil-recruiting cytokines.
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PMID:Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha- and interleukin-8 release in human bronchial epithelial cells. 1259 Nov 13

Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.
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PMID:Clinical pharmacokinetics of everolimus. 1474 18

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.
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PMID:Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. 1524 95

Sirolimus (SRL) is a substrate for cytochromes P-450 3A and P-glycoprotein, the product of the MDR1 gene. We postulated that single nucleotide polymorphisms (SNPs) of these genes could be associated with inter-individual variations in SRL requirements. We then evaluated in 149 renal transplant recipients the effect of polymorphisms CYP3A4*1/*1B, CYP3A5*1/*3 and MDR1 SNPs in exon 12, 21 and 26 on SRL concentration/dose (C/D) ratio 3 months after sirolimus introduction. SRL C/D ratio was significantly higher in patients treated with calcineurin inhibitors. The CYP3A4*1B and CYP3A5*1 alleles were present in 17% and 21% of patients, respectively. When treated with a SRL-based therapy and low-dose steroids, patients carrying the CYP3A4*1B or the CYP3A5*1 alleles required significantly more SRL to achieve adequate blood trough concentrations (p < 0.01 and p < 0.02, respectively). None of the MDR1 SNPs was associated with the SRL concentration/dose ratio. These findings suggest that the variations in SRL requirements are secondary to both genetic and non-genetic factors including pharmacokinetic interactions. In patients with SRL-based therapy, genotyping of the CYP3As genes may help to optimize the SRL management in transplant recipients.
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PMID:Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy. 1570 15

At present, the two calcineurin inhibitors-cyclosporine (CsA) and tacrolimus (FK506)-are among the most frequently used immunosuppressants in clinical transplantation. Both drugs share variable oral bioavailability, which necessitates intense drug monitoring. This variability is attributed to large interindividual differences in drug catabolism by cytochrome P450 3A4/5 (CYP3A4/5) and drug efflux by P-glycoprotein (PGP). In addition, the activity of both CYP3A4 and PGP can vary substantially within the same individual due to environmental factors such as concomitant intake of inducing/inhibiting medications (eg, rifampicin/sporanox) or food substances (eg, grapefruit juice). More recently, an inducing effect of methylprednisolone on intestinal and hepatic CYP3A4 has been shown. Also, an influence of gender on CYP3A4 activity (being higher in women) has been reported. Once CsA and FK506 are absorbed and reach the bloodstream, both drugs are avidly bound to erythrocytes (up to 95% for FK506 and 50% for CsA) and plasma proteins, leaving only a small fraction of circulating active drug. This phenomenon also limits further hepatic catabolism and hence clearance of drug, which is influenced by hematocrit and levels of plasma proteins such as albumin. The aim of the present study was to compare the influence of changing steroid doses, hematocrit, and albumin on trough and dose levels of FK506 versus CsA during the first year after transplantation. In addition, the evolution of trough and dose levels of FK506 versus CsA was stratified according to gender.
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PMID:Different evolution of trough and dose levels during the first year after transplantation for tacrolimus versus cyclosporine. 1596 36

Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4+PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.
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PMID:Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus. 1609 3

Cyclosporin A induces closure of the mitochondrial permeability transition pore. We aimed to investigate whether this closure results in concomitant increases in mitochondrial membrane potential (DeltaPsim) and the production of reactive oxygen species. Fluorescent probes were used to assess DeltaPsim (JC-1, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolyl-carbocyanine iodide), reactive oxygen species [DCF, 5- (and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester] and [Ca2+][Fluo-3, glycine N-[4-[6-[(acetyloxy)methoxy]-2,7-dichloro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-(acetyloxy)methyl ester] in human kidney cells (HK-2 cells) and in a line of human small cell carcinoma cells (GLC4 cells), because these do not express cyclosporin A-sensitive P-glycoprotein. We used transfected GLC4 cells expressing P-glycoprotein as control for GLC4 cells. NIM811 (N-methyl-4-isoleucine-cyclosporin) and PSC833 (SDZ-PSC833) were applied as selective mitochondrial permeability transition pore and P-glycoprotein blockers, respectively. To study the effect of cyclosporin A on mitochondrial function, we isolated mitochondria from fresh pig livers. Cyclosporin A and PSC833 induced a more than two-fold increase in JC-1 fluorescence in HK-2 cells, whereas NIM811 had no effect. None of the three substances induced a significant increase in JC-1 fluorescence in GLC4 cells. Despite this, cyclosporin A, NIM811 and PSC833 induced a 1.5-fold increase in DCF fluorescence (P<0.05) and a two-fold increase in Fluo-3 fluorescence (P<0.05). Studies in isolated mitochondria showed that blockage of mitochondrial permeability transition pores by cyclosporin A affected neither DeltaPsim, ATP synthesis, nor respiration rate. The mitochondrial permeability transition pore blockers cyclosporin A and NIM811, but also the non-mitochondrial permeability transition pore blocker PSC833, induced comparable degrees of reactive oxygen species production and cytosolic [Ca2+]. Neither mitochondria, effects on P-glycoprotein nor inhibition of calcineurin therefore play a role in cyclosporin A-induced oxidative stress and disturbed Ca2+ homeostasis.
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PMID:Cyclosporin A-induced oxidative stress is not the consequence of an increase in mitochondrial membrane potential. 1750 81

The calcineurin inhibitors cyclosporine and tacrolimus are widely used to prevent allograft rejection after transplantation. Since these drugs have narrow therapeutic windows and show considerable pharmacokinetic variability, therapeutic drug monitoring (TDM) is essential to avoid adverse effects such as nephrotoxicity while maximizing immunosuppressive efficacy. On the other hand, some patients experience acute rejection episodes or postoperative complications despite achieving therapeutic blood drug levels. Therefore, pharmacokinetic and pharmacodynamic factors by which to establish individualized dosage adjustment for these drugs should be identified. Recently, it was recognized that pharmacogenomics has the potential to facilitate personalized medicine by translating knowledge of human genome variability into rational therapeutics. In this paper, we review the population pharmacokinetic and pharmacogenomic analysis of tacrolimus, focusing on an efflux transporter P-glycoprotein (multidrug resistance 1 [MDR1/ABCB1]) and drug-metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5, and describe Bayesian forecasting to individualize the tacrolimus dose in de novo living-donor liver transplant recipients. Furthermore, the pharmacodynamic properties of tacrolimus and cyclosporine, which were evaluated by measuring calcineurin phosphatase activity in peripheral blood mononuclear cells, are reviewed in relation to an optimal monitoring strategy as well as a rational dosage regimen for these drugs.
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PMID:[Individualized dosage regimen of immunosuppressive drugs based on pharmacokinetic and pharmacodynamic analysis]. 1760 67


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