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)

Sirolimus is primarily used as a rescue agent in pediatric transplant recipients, particularly in cases of cyclosporine or tacrolimus toxicity. Preliminary data indicate a higher apparent oral clearance in younger children (4-10 years of age). Various drug interactions have been described between sirolimus and drugs that are substrates/inhibitors or inducers of CYP3A and the P-glycoprotein transporter. Close monitoring of trough sirolimus blood levels is therefore recommended for pediatric transplant recipients. In de novo adult kidney transplant recipients on triple therapy with cyclosporine, corticosteroids and sirolimus, a therapeutic window of 4-12 microg/l is recommended for sirolimus trough concentrations determined by HPLC or LC/MS-MS. In maintenance adult patients after conversion to a calcineurin inhibitor-free regimen, sirolimus trough concentrations of 5-10 microg/l are proposed in combination with mycophenolate mofetil. These therapeutic ranges may also serve as a guide for pediatric renal transplant recipients. The concept of C2 monitoring still needs to be critically evaluated in pediatric patients. The crucial importance of achieving an adequate cyclosporine exposure early after transplantation has been demonstrated for adult transplant recipients. A cyclosporine concentration taken 2 h after dosing is a good surrogate marker of the AUC0-4h in adults. Various clinical studies have shown that in pediatric patients, the C2 concentration shows a substantially better correlation with cyclosporine exposure compared to the trough level (C0). In an outcome study with pediatric renal transplant recipients, it could be demonstrated that the AUC(0-4h) was a predictor of acute rejection in the first 3 weeks after transplantation, whereas C2 levels showed no significant association. Abbreviated AUC strategies may be preferable for optimization of CsA exposure in pediatric patients.
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PMID:Immunosuppressive drug monitoring of sirolimus and cyclosporine in pediatric patients. 1518 89

Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435C-->T polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435C-->T and 2677G-->T/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity (chi2 = 10.5; P = 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donor's ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P = 0.034). A dominant role of the donor's ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.
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PMID:ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. 1577 50

1. The calcineurin inhibitor cyclosporine is widely used to prevent allograft rejection after solid organ transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual differences in the activity and expression of the metabolising enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp) contribute considerably to cyclosporine pharmacokinetics. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes. 2. The aim of the present study was to evaluate retrospectively the effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine dose adjusted trough blood concentration during the early period after renal transplantation in Chinese patients. 3. One hundred and six renal transplant recipients in China were genotyped by polymerase chain reaction-restriction fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and MDR1 C3435T. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Dose-adjusted trough blood concentrations (C(0)) were determined and compared among the different genotype groups. 4. The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T variant alleles were 0.005 (95% confidence interval (CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95% CI 0.526, 0.531), respectively, and these alleles exhibited incomplete linkage disequilibrium. The median cyclosporine dose-adjusted C(0) in CYP3A5*1/*1 genotype subjects (n = 6) was 14.8 ng/mL per mg per kg (range 11.1-26.8 ng/mL per mg per kg), in CYP3A5*1/*3 patients (n = 34) it was 23.7 ng/mL per mg per kg (range 9.0-61.0 ng/mL per mg per kg) and for CYP3A5*3/*3 patients (n = 66) it was 26.4 ng/mL per mg per kg (range 9.8-85.8 ng/mL per mg per kg; P = 0.012, Kruskal-Wallis test). Accordingly, cyclosporine dose-adjusted C0 was larger in CYP3A5 non-expressors than expressors in the first week after renal transplantation. In addition, wild-type homozygotes (n = 21) for MDR1 C3435T had a slight but significantly lower dose-adjusted C0 compared with heterozygotes (n = 58): 17.7 (10.3-60.8) versus 26.4 (9.0-67.3) ng/mL per mg per kg, respectively (P = 0.014, Mann-Whitney U-test). 5. In conclusion, the present study shows that genetic polymorphisms in CYP3A5 may be responsible, in part, for the large interindividual variability of cyclosporine pharmacokinetics during the early phase after renal transplantation in Chinese patients. Patients with the CYP3A5*3 variant genotype require a low dose of cyclosporine to reach target levels compared with those with the CYP3A5*1 allele.
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PMID:Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. 1704 20

In two separate pharmacokinetic studies, the drug interaction between immunosuppressive agents was examined in a total of 12 cardiac transplant recipients by conversion of the concomitant immunosuppressant. In six patients under continuous tacrolimus therapy, the concomitant drug azathioprine was converted to everolimus (PK-TAC study). No significant effect on tacrolimus pharmacokinetic parameters was observed. In the second study in which the patients were converted from cyclosporine to tacrolimus under continuous everolimus therapy (PK-EVL study), a significant decrease in everolimus predose concentration (from 4.2 to 2.3 microg/L), maximum concentration (from 9.1 to 5.9 microg/L), and area under the concentration time curve (mean values decreased from 64.2 to 33.7 microg*h/L) was found, indicating a lower everolimus exposure. A pharmacokinetic interaction between cyclosporine and everolimus has been described previously for healthy volunteers after single-dose application and presumably originates from a comparatively greater inhibition of hepatic CYP3A4 or P-glycoprotein efflux transporter with a low-dose cyclosporine regimen. Our results confirm this interaction under clinical conditions and suggest close drug monitoring when converting the calcineurin inhibitor under concomitant mammalian target of rapamycin-inhibitor therapy.
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PMID:Everolimus exposure in cardiac transplant recipients is influenced by concomitant calcineurin inhibitor. 1822 73

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.
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PMID:Calcineurin inhibitor nephrotoxicity. 1921 75

Concomitant use of immunosuppressive agents and antiretroviral drugs may lead to complex drug-drug interactions. The calcineurin inhibitor tacrolimus is metabolized by cytochrome P-450 3A4 (encoded by the CYP3A4 gene) and is a substrate of P-glycoprotein (encoded by the ABCB1 gene). Both pathways can be inhibited by protease inhibitors (PIs). The reduction in first-pass and postabsorptive metabolism of tacrolimus by PIs can lead to extreme prolongation of the elimination half-life and significantly increase tacrolimus trough levels. In a patient with human immunodeficiency virus (HIV)-associated focal segmental glomerulosclerosis leading to kidney cadaveric transplantation, HIV salvage therapy was started with the new PI darunavir and boosted with ritonavir, another PI. The reduction in first-pass and postabsorptive metabolism of tacrolimus by PIs led to a dramatic increase in tacrolimus trough levels and extreme prolongation of the elimination half-life. Trough levels of tacrolimus levels were as high as 106.7 ng/mL. A decrease in tacrolimus dosage to a single dose of 0.5 mg/wk, corresponding to 3.5% of the usual dose, enabled maintenance of stable tacrolimus trough levels. Our case highlights that coadministration of a PI and tacrolimus is feasible through intense reduction in dose and prolongation of the dosing interval of the calcineurin inhibitor. Complex drug interactions may become more frequent because more HIV-infected patients are undergoing transplantation and newer HIV drugs are being used. Close monitoring and excellent adherence are mandatory to avoid the risk of harm for the graft and patient.
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PMID:Drug-drug interaction in a kidney transplant recipient receiving HIV salvage therapy and tacrolimus. 1934 40

The calcineurin inhibitor cyclosporine is removed from lymphocytes by the drug efflux transporter P-glycoprotein (P-gp) encoded by the ABCB1 gene for which several single nucleotide polymorphisms (SNPs) have been identified. Of a total of 87 healthy volunteers genotyped for ABCB1 G2677T/A and C3435T SNPs, 10 GG-CC and 9 TT-TT individuals were selected and received a single oral dose of cyclosporine. Peripheral blood mononuclear cell (PBMC) ABCB1 mRNA expression, P-gp activity in CD4(+) and CD8(+) cells and the 24h cyclosporine pharmacokinetics in PBMCs and whole blood were determined. No correlation was observed between cyclosporine PBMC and whole blood levels (AUC(0-24), Spearman, r(S)=0.09, p=0.71). Intraindividual PBMC and whole blood levels followed parallel profiles that did not significantly differ with respect to t(max) (Wilcoxon, p=0.53) and t((1/2)) (p=0.49). Significant negative correlations between cyclosporine t((1/2)) in PBMCs and P-gp activity in CD4(+) (r(S)=-0.82, p=0.007) and CD8(+) (r(S)=-0.72, p=0.03) were observed among TT-TT subjects. Similarly, a negative correlation was detected in the GG-CC group between P-gp activity in CD4(+) and cyclosporine PBMC AUC(0-24) (r(S)=-0.69, p=0.03), as well as PBMC to whole blood AUC(0-24) ratio (r(S)=-0.60, p=0.07). Tested ABCB1 genotypes had no influence on cyclosporine pharmacokinetic parameters in PBMCs and whole blood. The haplotypes investigated were neither significantly correlated with PBMC ABCB1 mRNA expression nor with P-gp activity in CD4(+) and CD8(+). In conclusion, cyclosporine PBMC pharmacokinetics was influenced by P-gp activity and cyclosporine whole blood concentrations did not predict PBMC drug levels, suggesting that despite values in the therapeutic range, some subjects could have inadequate intracellular drug levels.
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PMID:Influence of ABCB1 gene polymorphisms and P-glycoprotein activity on cyclosporine pharmacokinetics in peripheral blood mononuclear cells in healthy volunteers. 1935 75

Currently, >50% of candidates for solid organ transplantation in Europe and the US are aged >50 years while approximately 15% of potential recipients are aged >or=65 years. Elderly transplant candidates are characterized by specific co-morbidity profiles that compromise graft and patient outcome after transplantation. The presence of coronary artery or peripheral vascular disease, cerebrovascular disease, history of malignancy, chronic obstructive lung disease or diabetes mellitus further increases the early post-transplant mortality risk in elderly recipients, with infections and cardiovascular complications as the leading causes of death. Not only are elderly patients more prone to developing drug-related adverse effects, but they are also more susceptible to pharmacokinetic and pharmacodynamic drug interactions because of polypharmacy. The majority of currently used immunosuppressant drugs in organ transplantation are metabolized by cytochrome P450 (CYP) or uridine diphosphate-glucuronosyltransferases and are substrates of the multidrug resistance (MDR)-1 transporter P-glycoprotein, the MDR-associated protein 2 or the canalicular multispecific organic anion transporter, which predisposes these immunosuppressant compounds to specific interactions with commonly prescribed drugs. In addition, important drug interactions between immunosuppressant drugs have been identified and require attention when choosing an appropriate immunosuppressant drug regimen for the frail elderly organ recipient. An age-related 34% decrease in total body clearance of the calcineurin inhibitor ciclosporin was observed in elderly renal recipients (aged >65 years) compared with younger patients, while older recipients also had 44% higher intracellular lymphocyte ciclosporin concentrations. Similarly, using a Bayesian approach, an inverse relationship was noted between sirolimus clearance and age in stable kidney recipients. Ciclosporin and tacrolimus have distinct pharmacokinetics, but both are metabolized by intestinal and hepatic CYP3A4/3A5 and transported across the cell membrane by P-glycoprotein. The most common drug interactions with ciclosporin are therefore also observed with tacrolimus, but the two drugs do not interact identically when administered with CYP3A inhibitors or inducers. The strongest effects on calcineurin-inhibitor disposition are observed with azole antifungals, macrolide antibacterials, rifampicin, calcium channel antagonists, grapefruit juice, St John's wort and protease inhibitors. Drug interactions with mycophenolic acids occur mainly through inhibition of their enterohepatic recirculation, either by interference with the intestinal flora (antibacterials) or by limiting drug absorption (resins and binders). Rifampicin causes a reduction in mycophenolic acid exposure probably through induction of uridine diphosphate-glucuronosyltransferases. Proliferation signal inhibitors (PSIs) such as sirolimus and everolimus are substrates of CYP3A4 and P-glycoprotein and have a macrolide structure very similar to tacrolimus, which explains why common drug interactions with PSIs are comparable to those with calcineurin inhibitors. Ciclosporin, in contrast to tacrolimus, inhibits the enterohepatic recirculation of mycophenolic acids, resulting in significantly lower concentrations and hence risk of underexposure. Therefore, when switching from tacrolimus to ciclosporin and vice versa or when reducing or withdrawing ciclosporin, this interaction needs to be taken into account. The combination of ciclosporin with PSIs requires dose reductions of both drugs because of a synergistic interaction that causes nephrotoxicity when left uncorrected. Conversely, when switching between calcineurin inhibitors, intensified monitoring of PSI concentrations is mandatory. Increasing age is associated with structural and functional changes in body compartments and tissues that alter absorptive capacity, volume of distribution, hepatic metabolic function and renal function and ultimately drug disposition. While these age-related changes are well-known, few specific effects of the latter on immunosuppressant drug metabolism have been reported. Therefore, more clinical data from elderly organ recipients are urgently required.
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PMID:Immunotherapy in elderly transplant recipients: a guide to clinically significant drug interactions. 1972 47

The contributions of donor kidney quality (partially determined by donor age), allograft rejection, and calcineurin inhibitor nephrotoxicity on the progression of histologic damage of renal allografts are not completely defined. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not known but may include variability in drug transport and metabolism. In a prospective cohort of 252 adult renal allograft recipients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids, we studied 744 renal allograft biopsies obtained regularly from time of transplantation for 3 yr. We assessed determinants of histologic evolution, including tacrolimus exposure, renal P-glycoprotein (ABCB1) expression, and polymorphisms in the CYP3A4, CYP3A5, and ABCB1 genes. Within the first 3 yr after transplantation, we noted a progressive increase in interstitial fibrosis, tubular atrophy, glomerulosclerosis, and vascular intimal thickening. Older donor age, absence of P-glycoprotein expression at the apical membrane of tubular epithelial cells, and combined donor-recipient homozygosity for the C3435T variant in ABCB1 significantly associated with increased susceptibility to chronic allograft damage independent of graft quality at implantation. Changes in graft function over time reflected these associations with donor age and ABCB1 polymorphisms, but it was acute T cell-mediated and antibody-mediated rejection that determined early graft survival. In conclusion, the effects of older donor age reach beyond the quality of the allograft at implantation and continue to be important for histologic evolution in the posttransplantation period. In addition, ABCB1 genotype and expression of P-glycoprotein in renal tubular epithelial cells determine susceptibility to chronic tubulointerstitial damage of transplanted kidneys.
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PMID:Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts. 1979 70

Thiopurines, methotrexate and the calcineurin inhibitors cyclosporin A and tacrolimus are classical immunosuppressive treatment modalities for inflammatory bowel disease (IBD). Since a high inter-patient variability exists in drug efficacy and toxicity, their application requires the knowledge of appropriate indications as well as strategies for individualization of dosage and monitoring for adverse events. Results of pharmacogenetic studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics and pharmacodynamics may be helpful for the optimization of individualized therapy. Although 85-95% of patients worldwide present with the homozygote thiopurine S-methyltransferase (TPMT) wild-type genotype and a normal enzyme activity, cost-benefit analyses suggest assessment of TPMT enzyme activity prior to thiopurine therapy for IBD to prevent life-threatening toxicity. Monitoring of 6-mercaptopurine metabolites is a helpful, but not an indispensable tool in thiopurine non-responders to discriminate poor adherence and under-dosing from pharmacogenetic thiopurine resistance and thiopurine refractory disease. Response to and adverse events of methotrexate therapy are hard to predict. Pharmacogenetic indices of methotrexate metabolization have been evaluated in rheumatoid arthritis (RA) but not in IBD yet. In contrast to RA, concentration of methotrexate polyglutamates correlates positively with non-response and adverse effects in IBD. Calcineurin inhibitor metabolism is mainly controlled by cytochrome P-450 isoenzymes 3A4/3A5 and P-glycoprotein that underlie a variety of gene polymorphisms and are susceptible to drug interactions. Independent from pharmacokinetic alterations a MDR1 polymorphism may predict cyclosporin failure in severe ulcerative colitis. Frequent monitoring of whole blood levels is required since efficacy and toxicity are dose-dependent.
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PMID:Drug monitoring in inflammatory bowel disease: helpful or dispensable? 1978 71


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