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)

Drug-induced QT interval prolongation is a condition likely to be aggravated by diabetes. The objective of this study was to evaluate how glucose concentration may modulate drug effects on ventricular repolarization and on cardiac repolarizing potassium currents. Guinea pig hearts were Langendorff-retroperfused and monophasic action potential duration (MAPD) was measured. Glucose (1, 5 or 20 mmol/L) was tested with either dofetilide (a specific I(Kr) blocker), chromanol 293B (a specific I(Ks) blocker) or both. Effects of glucose (1, 5 or 20 mmol/L) on I(Kr) blockade mediated by dofetilide were also measured in HERG-transfected HEK293 cells in the absence vs presence of the P-glycoprotein drug transporter, using the whole cell patch-clamp technique. Our results suggest that both hypo- and hyperglycemia potentiate the MAPD-prolonging and I(Kr)-blocking properties of dofetilide. P-glycoprotein drug extrusion efficacy appears as a key determinant of dofetilide's I(Kr)-blocking effect. This efficacy appears to be affected by glucose concentration, particularly hyperglycemia.
J Mol Cell Cardiol 2009 Aug
PMID:Impact of glucose concentration on cardiac ventricular repolarization under I Kr/I Ks blocking agents. 1923 95

Recently, drug interactions with grapefruit juice (GFJ) have received considerable attention from basic scientists, physicians, industry and drug regulatory agencies. GFJ has been shown to inhibit cytochrome P-450 3A4 isoenzyme and P-glycoprotein transporters in the intestine and liver. The GFJ-induced inhibitory effects are considered to be responsible for alterations in drug bioavailability, and pharmacokinetic and pharmacodynamic changes when drugs are ingested concurrently with GFJ. However, little or no interaction is observed when GFJ is taken concomitantly with parentally administered drugs. It is well known that risk factors for cardiovascular disease increase with advancing age, while hepatic metabolic activity decreases in elderly individuals. It is, therefore, possible that the combination of GFJ and cardiovascular medications may pose a health risk, especially in elderly patients. A number of studies have shown interactions of GFJ with cardiovascular drugs such as calcium-channel blockers, angiotensin II receptor antagonists, beta-blockers, and statins. Such interactions are likely to change the pharmacokinetics and pharmacodynamics of these drugs, consequently causing undesirable health effects. Therefore, health care professionals and the public need to be advised of the potential risks associated with the concomitant use of GFJ and interacting medications, especially cardiovascular drugs and agents with a narrow therapeutic index. This review focuses on the adverse interactions of GFJ and cardiovascular medications, and the proposed underlying mechanisms of such interactions.
Exp Clin Cardiol 2003
PMID:Interactions of grapefruit juice and cardiovascular medications: A potential risk of toxicity. 1964 58

The thienopyridine antiplatelet agent clopidogrel is an effective drug for the prevention of vascular events. However, data has accumulated over time to suggest it is prone to significant interpatient variability. While there are several factors that contribute to this, one of the most important is variability in forming the active metabolite necessary for clopidogrel function. Several enzymes are involved in formation of this metabolite, and two, CYP2C19 and P-glycoprotein, appear to have alleles that both occur frequently in the population and have a clinically significant impact. Patients carrying these alleles can be identified, but it remains to be determined if this information is necessary or sufficient for risk stratification. Furthermore, if patients with high-risk alleles are identified, it is unclear how treatment should be adjusted.
Clin Med Insights Cardiol 2010 Dec 01
PMID:Clopidogrel: a pharmacogenomic perspective on its use in coronary artery disease. 2115 50

We present a case of digoxin toxicity in the context of dehydration, renal dysfunction and concomitant use of the macrolide antibiotic, clarithromycin, which is known to inhibit P-glycoprotein-mediated efflux mechanisms of digoxin. A focused review of the literature is presented. Health care providers need to be vigilant of this mechanism of drug-drug interaction, which is also relevant to other commonly used cardiovascular drugs.
Can J Cardiol
PMID:Digoxin toxicity precipitated by clarithromycin use: case presentation and concise review of the literature. 2190 34

Safe and effective stroke prevention in atrial fibrillation (AF) is crucial as the number of patients with this condition continues to increase. Several novel oral anticoagulants are being developed as replacements for warfarin for this indication. Direct factor Xa inhibitors comprise the largest class of oral anticoagulants in development; the inhibition of factor Xa is recognized to be a promising target for therapeutic anticoagulation, partly because of its location in the coagulation cascade. Apixaban, betrixaban, edoxaban, and rivaroxaban are small-molecule, selective inhibitors that directly and reversibly bind to the active site of factor Xa. Their pharmacokinetic and pharmacodynamic profiles vary, which might allow patient-specific therapy. Several of these agents have been tested in clinical trials for various indications, including AF, with favorable results. In particular, apixaban and rivaroxaban have shown superiority and noninferiority, respectively, to warfarin in phase III clinical trials for stroke prevention in AF. These agents have also been shown to be safe in terms of bleeding risk. Despite these advantages, factor Xa inhibitors have several characteristics, such as potential interactions with other drugs (inhibitors of cytochrome P450 and P-glycoprotein) and the inability to reverse their anticoagulant effects, as well as concerns about poor patient compliance, which must be considered when initiating patients on a novel factor Xa inhibitor.
Nat Rev Cardiol 2012 Feb 28
PMID:Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. 2237 Nov 4

Atrial fibrillation (AF) is an independent risk factor for ischemic stroke occurrence, severity, recurrence, and mortality. Anticoagulation therapy for the prevention of thromboembolism is critical in patients with AF who are at risk of stroke. Warfarin has been an efficacious anticoagulant for this purpose, but its use has been limited by frequent laboratory monitoring, drug interactions, unpredictable individual response, delayed onset of action, and bleeding. Apixaban is the second oral direct selective factor Xa inhibitor approved for the prevention of stroke/systemic embolism in patients with nonvalvular AF. It was significantly better than aspirin in reducing stroke (ischemic or hemorrhagic) or systemic embolism without increasing the risk of major bleeding in patients with AF who were at increased risk of stroke and for whom warfarin was unsuitable. In a randomized, double-blind trial that was originally designed to test for noninferiority, apixaban was superior to warfarin (target international normalized ratio 2-3) in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with AF. Apixaban has a half-life of about 12 hours, and the normal dosage is 5 mg orally twice daily. However, it may be reduced to 2.5 mg twice daily based on individual factors of the patient (age, renal function, and body weight) and the concomitant use of potent dual inhibitors of cytochrome P450 3A4 and P-glycoprotein. Similar to other novel oral anticoagulants (dabigatran and rivaroxaban), apixaban has no reversal agent for its anticoagulant effect. Overall, apixaban is a safe and efficacious alternative for stroke prophylaxis in high-risk patients who have AF and who are unable to achieve therapeutic goals with warfarin therapy.
Cardiol Rev
PMID:Apixaban: a new factor Xa inhibitor for stroke prevention in patients with nonvalvular atrial fibrillation. 2353 30

Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interindividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabigatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alternative therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmacokinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect of clinical variables such as age, renal function, dosing interval, and drug metabolism (CYP3A4) and transport (P-glycoprotein), we might be able to better predict the risk for sub- and supratherapeutic anticoagulation response and individualize OAC selection and dosing.
Can J Cardiol 2013 Jul
PMID:Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. 2379 May 95

The purpose of this study was to demonstrate experimentally that alterations of in vivo transporter function at the blood-brain barrier (BBB) in disease and during pharmacotherapy can be reconstructed from in vitro data based on our established pharmacoproteomic concept of reconstructing in vivo function by integrating intrinsic transport activity per transporter molecule and absolute protein expression level at the BBB. Pentylenetetrazole (PTZ)-kindled and spontaneous model of epilepsy (EL) mice were used as models of chemically induced and spontaneous epilepsy, respectively. A mouse model of antiepileptic drug treatment was prepared by consecutive 5-week administration of phenytoin (PHT). Quantitative targeted absolute proteomic analysis of 31 membrane proteins showed that P-glycoprotein (P-gp/mdr1a) protein expression levels were significantly increased in brain capillaries of PTZ (129%), EL (143%), and PHT mice (192%) compared with controls. The brain-to-plasma concentration ratios (Kp brain) of P-gp/mdr1a substrate verapamil were 0.563, 0.394, 0.432, and 0.234 in control, PTZ, EL, and PHT mice, respectively. In vivo P-gp/mdr1a function at the BBB was reconstructed from the measured P-gp/mdr1a protein expression levels and intrinsic transport activity for verapamil per P-gp/mdr1a previously reported by our group. Then, the reconstructed P-gp/mdr1a functional activities were integrated with unbound fractions of verapamil in plasma and brain to reconstruct Kp brain of verapamil. In all mice, reconstructed Kp brain values agreed well with the observed values within a 1.21-fold range. These results demonstrate that altered P-gp functions at the BBB in epilepsy and during pharmacotherapy can be reconstructed from in vitro data by means of our pharmacoproteomic approach.
...
PMID:Pharmacoproteomics-based reconstruction of in vivo P-glycoprotein function at blood-brain barrier and brain distribution of substrate verapamil in pentylenetetrazole-kindled epilepsy, spontaneous epilepsy, and phenytoin treatment models. 2506 Nov 62

In the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, dronedarone use was associated with an excess risk of stroke, cardiovascular death and hospitalizations. However, an increased level in the serum digoxin level was observed in the dronedarone arm, as it is a potent inhibitor of the P-glycoprotein transport system. The PALLAS subanalysis suggests that digoxin-dronedarone interaction was responsible for the higher arrhythmic death rate observed in the trial. These data are consistent with several other studies that demonstrate the potential hazard of the use of digoxin in heart failure and/or atrial fibrillation. One must consider other safer alternatives before prescribing digoxin in atrial fibrillation patients.
Glob Cardiol Sci Pract 2015
PMID:Dronedarone-digoxin interaction in PALLAS: A foxglove connection? 2583 Jan 48

Dabigatran etexilate is a substrate of the P-glycoprotein (adenosine triphosphate-binding cassette subfamily B member 1) transport system and is subject to interactions with medications that induce or inhibit this system. The clinical relevance of the interaction between dabigatran and phenytoin has not been well described. We report a case of left atrial thrombus in a patient receiving concomitant dabigatran etexilate and phenytoin, which is a P-glycoprotein inducer. This case illustrates the potential clinical significance of the interactions of medications that affect P-glycoprotein and dabigatran.
Can J Cardiol 2017 04
PMID:Development of Left Atrial Thrombus After Coadministration of Dabigatran Etexilate and Phenytoin. 2806 39


1 2 Next >>