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)

Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125 mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30 L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3-5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal impairment (creatinine clearance 15-30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and beta-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin. In healthy subjects, bosentan doses >300 mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.
...
PMID:Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. 1556 89

Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy. Following administration of an oral solution or IR capsule, peak plasma concentrations (C(max)) are observed within 1 hour. After administration of radiolabelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61-64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180 L. Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state C(max) and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment. Ranolazine is a weak inhibitor of CYP3A, and increases AUC and C(max) for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by CYP3A inhibitors ranging from 1.5-fold for diltiazem 180 mg once daily to 3.9-fold for ketoconazole 200 mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.
...
PMID:Clinical pharmacokinetics of ranolazine. 1664 Apr 53

Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference has been attributed to bodyweight. However, the pharmacodynamics of ceftobiprole are similar in males and females, and dosing adjustments are not required based on gender. In patients with moderate to severe renal impairment, systemic clearance of ceftobiprole correlated well with creatinine clearance. For these patients, dose adjustments for the treatment of infections caused by target pathogens, including MRSA, should be based on creatinine clearance. Ceftobiprole is undergoing clinical evaluation in phase III trials in patients with complicated skin and skin structure infections, patients with nosocomial pneumonia, and community-acquired pneumonia in hospitalized patients.
...
PMID:Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity. 1807 16

The succinate salt of solifenacin, a tertiary amine with anticholinergic properties, is used for symptomatic treatment of overactive bladder. Solifenacin peak plasma concentrations of 24.0 and 40.6 ng/mL are reached 3-8 hours after long-term oral administration of a 5 or 10 mg solifenacin dose, respectively. Studies in healthy adults have shown that the drug has high absolute bioavailability of about 90%, which does not decrease with concomitant food intake. Solifenacin has an apparent volume of distribution of 600 L, is 93-96% plasma protein bound, and probably crosses the blood-brain barrier. Solifenacin is eliminated mainly through hepatic metabolism via cytochrome P450 (CYP) 3A4, with about only 7% (3-13%) of the dose being excreted unchanged in the urine. Solifenacin metabolites are unlikely to contribute to clinical solifenacin effects. In healthy adults, total clearance of solifenacin amounts to 7-14 L/h. The terminal elimination half-life ranges from 33 to 85 hours, permitting once-daily administration. Urinary excretion plays a minor role in the elimination of solifenacin, resulting in renal clearance of 0.67-1.51 L/h. Solifenacin does not influence the activity of CYP1A1/2, 2C9, 2D6 and 3A4, and shows a weak inhibitory potential for CYP2C19 and P-glycoprotein in vitro; however, clinical drug-drug interactions with CYP2C19 and P-glycoprotein substrates are very unlikely. Exposure to solifenacin is increased about 1.2-fold in elderly subjects and about 2-fold in subjects with moderate hepatic and severe renal impairment, as well as by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg/day. The full therapeutic effects of solifenacin occur after 2-4 weeks of treatment and are maintained upon long-term therapy. Although solifenacin pharmacokinetics display linearity at doses of 5-40 mg, no obvious dose dependency was observed in efficacy and tolerability studies. The efficacy of solifenacin (5 or 10 mg/day) is at least equal to that of extended-release (ER) tolterodine (4 mg/day) in reducing the mean number of micturitions per 24 hours and urgency episodes, and in increasing the volume voided per micturition. Solifenacin (5 mg/day) appears to be superior to ER tolterodine (4 mg/day) in reducing incontinence episodes (mean -1.30 vs -0.90, p = 0.018) and is superior to propiverine (20 mg/day) at the dose of 10 mg/day in reducing urgency (-2.30 vs -2.78, p = 0.012) and nocturia episodes. Based on withdrawal rates due to adverse effects during the 52-week treatment period, solifenacin appears to have better tolerability than immediate-release (IR) oxybutynin 10-15 mg/day and IR tolterodine 4 mg/day. With regard to the pharmacokinetics of solifenacin, and for safety reasons, doses exceeding 5 mg/day are not recommended for patients with moderate hepatic impairment (Child-Pugh score 7-9), patients with severe renal impairment (creatinine clearance <30 mL/min) and subjects undergoing concomitant therapy with CYP3A4 inhibitors.
...
PMID:Clinical pharmacokinetics and pharmacodynamics of solifenacin. 1956 12

Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach, etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin and alpha(1)-acid glycoprotein and shows a relatively long elimination half-life of 30-40 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated by uridine diphosphate glucuronosyltransferase. Renal elimination of etravirine is negligible. Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of etravirine has been well characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or mild to moderate hepatic impairment. Race, sex, bodyweight and age do not affect the pharmacokinetics of etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the pharmacokinetics of etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the safety profile of etravirine.
...
PMID:Clinical pharmacokinetics and pharmacodynamics of etravirine. 1972 91

Digoxin has a narrow therapeutic margin and potentially life-threatening cardiac adverse effects. Gastrointestinal disorders, neuropsychological disorders and bradycardia are warning signs. Some drug combinations can aggravate the cardiac adverse effects of digoxin, or reduce its efficacy. We reviewed the literature, using the standard Prescrire methodology, in order to examine which drugs are involved in these interactions, and the mechanisms involved. Most relevant data are based on small pharmacokinetic studies or detailed case reports. The adverse effects of digoxin are potentiated by renal impairment, which may be pre-existing or due to nephrotoxic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor antagonists and ciclosporin. Some coadministered drugs such as macrolides and cardiovascular drugs (especially amiodarone) can cause digoxin overdose through pharmacokinetic interactions. The mechanism most often implicated is inhibition of P-glycoprotein, of which digoxin is a substrate. Hypercalcaemia and hypokalaemia inducing drugs, heart-rate lowering drugs, and drugs that prolong the QT interval or slow cardiac conduction can potentiate the cardiac adverse effects of digoxin. Plasma concentration of digoxin is not affected. Several drugs, including sucralfate, acarbose, cytotoxic agents, and enzyme inducers, can reduce digoxin plasma concentrations. This effect is attributed to decreased gastrointestinal absorption or increased elimination of digoxin. In practice, patients treated with digoxin, and their caregivers, should be aware that digoxin has a narrow therapeutic margin and frequent and potentially severe adverse effects. Close clinical monitoring is necessary to detect early warning signs (bradycardia and gastrointestinal or neurological disorders). Digoxin assay alone is not always sufficient. Special care is required for patients with renal failure, the elderly and patients receiving potentially interacting drugs.
...
PMID:Digoxin: serious drug interactions. 2056 89

Linagliptin is a selective, competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the USA, Japan and Europe for the treatment of type 2 diabetes. It has non-linear pharmacokinetics and, unlike other DPP-4 inhibitors, a largely non-renal excretion route. It was hypothesised that P-glycoprotein (P-gp)-mediated intestinal transport could influence linagliptin bioavailability, and might contribute to its elimination. Two studies evaluated the role of P-gp-mediated transport in the bioavailability and intestinal secretion of linagliptin in rats. In the bioavailability study, male Wistar rats received single oral doses of linagliptin, 1 or 15 mg/kg, plus either the P-gp inhibitor, zosuquidar trihydrochloride, or vehicle. For the intestinal secretion study, rats underwent bile duct cannulation, and urine, faeces, and bile were collected. At the end of the study, gut content was sampled. Inhibition of intestinal P-gp increased the bioavailability of orally administered linagliptin, indicating that this transport system plays a role in limiting the uptake of linagliptin from the intestine. This effect was dependent on linagliptin dose, and could play a role in its non-linear pharmacokinetics after oral dosing. Systemically available linagliptin was mainly excreted unchanged via bile (49% of i.v. dose), but some (12%) was also excreted directly into the gut independently of biliary excretion. Thus, direct excretion of linagliptin into the gut may be an alternative excretion route in the presence of liver and renal impairment. The primarily non-renal route of excretion is likely to be of benefit to patients with type 2 diabetes, who have a high prevalence of renal insufficiency.
...
PMID:Excretion of the dipeptidyl peptidase-4 inhibitor linagliptin in rats is primarily by biliary excretion and P-gp-mediated efflux. 2219 11

Edoxaban is a novel, orally available, highly specific direct inhibitor of factor Xa and is currently being developed for the treatment and prevention of venous thromboembolism and prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objectives of the present analyses were to characterise edoxaban population pharmacokinetics (PPK) and identify potential intrinsic and extrinsic factors affecting variability in edoxaban exposure, determine if there are relationships between edoxaban pharmacokinetics or biomarkers and the risk of bleeding in patients with NVAF using an exposure-response model, and to use the PPK and exposure-response model to support dose selection for a phase III trial of edoxaban in patients with NVAF. PPK analysis of data from 1,281 edoxaban-dosed subjects with intrinsic factors such as renal impairment or NVAF and extrinsic factors such as concomitant medications revealed significant effects of renal impairment and concomitant strong P-glycoprotein (P-gp) inhibitors on the pharmacokinetics of edoxaban. Exposure-response analysis found that in patients with NVAF, the incidence of bleeding events increased significantly with increasing edoxaban exposure, with steady-state minimum concentration (Cmin,ss) showing the strongest association. Clinical trial simulations of bleeding incidence were used to select 30 mg and 60 mg once-daily edoxaban with 50% dose reductions for patients with moderate renal impairment or receiving concomitant strong P-gp inhibitors as the treatment regimens in the ENGAGE AF-TIMI 48 (NCT00781391) trial.
...
PMID:Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. 2239 55

For patients with atrial fibrillation and a high risk of thrombosis, the standard prophylaxis is warfarin, an anticoagulant, at a dose adjusted to the INR. Warfarin and aspirin are both reasonable choices for patients with a moderate risk of thrombosis. Dabigatran, an oral anticoagulant that inhibits thrombin, has been authorised for patients with atrial fibrillation and a moderate or high risk of thrombosis, without associated valvular abnormalities. Clinical evaluation of dabigatran is based on a randomised "non-inferiority" trial comparing two doses of dabigatran (110 mg and 150 mg) taken twice daily, and adjusted-dose warfarin, in 18 113 patients treated for an average of 21 months. Overall mortality was about 4% per year and did not differ between the 3 groups. There was a greater reduction in the annual incidence of stroke or systemic embolism with the higher dose of dabigatran (1.1%) than with warfarin (1.7%). This is not the case for the lower dose (1.5%). In patients with good INR control, the difference in favour of the higher dose of dabigatran was no longer statistically significant. All-cause treatment discontinuation rates were higher with dabigatran than with warfarin (21% versus 17%, p<0.001). The incidence of serious bleeding did not differ statistically between warfarin and the higher dose of dabigatran (3.57% versus 3.32%), but was lower with the lower dose of dabigatran (2.87%). Compared with warfarin, dabigatran appears to be associated with about a 0.2% excess of myocardial infarction (0.73% versus 0.53%). Dyspepsia is also more frequent with dabigatran (6% versus 1.4%). Hepatic adverse effects appear to be mild but need to be monitored. The effects of dabigatran are potentiated by combination with P-glycoprotein inhibitors and drugs that impair renal function. Combination with other antithrombotic agents should also be avoided. Treatment with dabigatran does not require monitoring of haemostasis, whereas vitamin K inhibitors necessitate close INR monitoring. In contrast, renal function must be monitored, as renal impairment increases the risk of bleeding. Unlike vitamin K antagonists, there is no antidote for dabigatran overdose. In practice, warfarin remains the standard drug for patients with atrial fibrillation and a moderate or high risk of thrombosis. Aspirin is an alternative for moderate-risk patients. When the risk is significant and the INR cannot be maintained within the target range despite close monitoring, dabigatran is the alternative to warfarin, provided the patient is closely monitored, especially for changes in renal function.
...
PMID:Dabigatran and atrial fibrillation: the alternative to warfarin for selected patients. 2241 15

Telaprevir is an inhibitor of the HCV NS3/4A protease. When used in combination with pegylated interferon and ribavirin, telaprevir has demonstrated a substantial increase in sustained virological response compared with pegylated interferon and ribavirin used alone. Telaprevir has good oral bioavailability, which is enhanced when administered with food. Telaprevir is extensively metabolized and primarily eliminated via faeces. No dose adjustment of telaprevir is needed in patients with mild to severe renal impairment or mild liver impairment. Telaprevir is a substrate and inhibitor of cytochrome P450 3A and P-glycoprotein and, thus, might interact with coadministered drugs that affect or are affected by these metabolic/transport pathways. This article reviews the pharmacokinetic and drug interaction profile of telaprevir.
...
PMID:Telaprevir: pharmacokinetics and drug interactions. 2295 56


1 2 3 4 Next >>

---