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)

The mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for therapeutic drug monitoring (TDM). Exposure-response analyses of data from early fixed-dose trials demonstrated that rates of biopsy-proven acute rejection (BPAR) are significantly higher if everolimus C0 declines below 3 ng/mL, an observation confirmed in subsequent concentration-controlled trials. Evidence for the most favorable upper limit is less clear but with reduced-exposure calcineurin inhibitor (CNI) therapy, an upper limit of 8 ng/mL appears to balance efficacy and safety outcomes. The recommended C0 range is 3-8 ng/mL in kidney, liver and heart transplantation patients, based on LC-MS/MS monitoring in whole blood. Randomized clinical trials based on this target range have demonstrated rates of BPAR comparable to a regimen of mycophenolic acid with standard-exposure CNI. Everolimus exhibits moderate intrapatient pharmacokinetic variability, and it can be challenging to maintain stable concentrations within target range in some individuals. Many factors can influence everolimus exposure for a given dose, including hepatic function, activity of the drug efflux pump P-glycoprotein, the rate of everolimus metabolism, drug-drug interactions (predominantly with CYP3A4 and P-glycoprotein inhibitors, including cyclosporine), intake of fatty food, and patient adherence to the prescribed regimen. Trough concentration levels should be monitored 4-5days after the first dose and after any change in everolimus dose, with additional monitoring in response to any change in concomitant medication or other clinical circumstances which could alter everolimus exposure. Although LC-MS/MS is the gold standard for everolimus monitoring, various immunoassays are widely used due to their relative simplicity and lower cost, and results can show considerable discrepancies with reference methods due to issues such as interassay variability and cross-reactivity. Method standardization will be important in the future to improve the consistency and reproducibility of results between centers. In conclusion, based on an extensive program of clinical trials, the optimal exposure range for everolimus in combination with reduced-exposure CNI therapy has been established and can be achieved in most transplant recipients through careful, planned TDM.
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PMID:Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation. 2827 67

Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.
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PMID:Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation. 2995 Jun 13

Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regimens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower incidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibility factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT.
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PMID:Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity. 3138 65


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