Extension de temps QT
Effets indésirables des médicaments
Variantes ✨Pour l'évaluation intensive en calcul des variantes, veuillez choisir l'abonnement standard payant.
Explications pour les patients
Les changements d'exposition mentionnés sont liés aux changements de la courbe concentration plasmatique en fonction du temps [ASC]. L'exposition à la simvastatine augmente à 1524%, lorsqu'il est associé à la érythromycine (325%) et à la amiodarone (157%). Puisque la substance est un promédicament, on s'attendrait plutôt à une efficacité réduite. L'exposition à la érythromycine augmente à 150%, lorsqu'il est associé à la simvastatine (106%) et à la amiodarone (141%). Nous n'avons détecté aucune modification de l'exposition à la amiodarone. Nous ne pouvons actuellement pas estimer l'influence de la érythromycine et de la simvastatine.
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La érythromycine a une faible biodisponibilité orale [ F ] de 24%, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer de manière significative avec une interaction. La demi-vie terminale [ t12 ] est assez courte à 2.3 heures et des taux plasmatiques constants [ Css ] sont atteints rapidement. La liaison aux protéines [ Pb ] est modérément forte à 73% et le volume de distribution [ Vd ] est de 56 litres, c'est pourquoi, à un taux d'extraction hépatique moyen de 0,9, le débit sanguin hépatique [Q] et une modification de la liaison aux protéines [Pb] sont pertinents. Le métabolisme s'effectue principalement via le CYP3A4 et le transport actif s'effectue en partie via MRP2 et PGP.
La simvastatine a une faible biodisponibilité orale [ F ] de 5%, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer de manière significative avec une interaction. La demi-vie terminale [ t12 ] est de 7.9 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est 96.5% forte et le volume de distribution [ Vd ] est de 46 litres dans la fourchette moyenne, Le métabolisme s'effectue principalement via le CYP3A4 et le transport actif s'effectue en partie via BCRP, MRP2 et PGP.
La amiodarone a une biodisponibilité orale moyenne [ F ] de 55%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est assez longue à 1884 heures et des taux plasmatiques constants [ Css ] ne sont atteints qu’après plus de 7536 heures. La liaison aux protéines [ Pb ] est 96% forte. Le métabolisme a lieu via le CYP2C8 et le CYP3A4, entre autres et le transport actif se fait notamment via PGP.
|Les scores||∑ Points||éry||sim||ami|
|Effets sérotoninergiques a||0||Ø||Ø||Ø|
Évaluation: Selon nos connaissances, ni la érythromycine, simvastatine ni la amiodarone n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||éry||sim||ami|
Évaluation: Selon nos résultats, ni la érythromycine, simvastatine ni la amiodarone n'augmentent l'activité anticholinergique.
Extension de temps QT
|Les scores||∑ Points||éry||sim||ami|
Évaluation: En association, la érythromycine et la amiodarone peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes. Nous ne connaissons aucun potentiel d'allongement de l'intervalle QT pour la simvastatine.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||éry||sim||ami|
|La nausée||26.5 %||+||5.4↑||21.5|
|Douleur abdominale||8.2 %||+||7.3↑||n.a.|
|Perte d'appétit||7.4 %||+||n.a.||6.5|
|Problème de coordination||6.5 %||n.a.||n.a.||6.5|
Paresthésie (6.5%): amiodarone
Mal de crâne (5%): simvastatine
Neuropathie périphérique: amiodarone
Pseudotumeur cérébrale: amiodarone
Crise d'épilepsie: érythromycine
Vision floue (6.5%): amiodarone
Névrite optique: amiodarone
Perte visuelle: amiodarone
Hyperthyroïdie (2%): amiodarone
Syndrome de détresse respiratoire aiguë (2%): amiodarone
Fibrose pulmonaire: amiodarone
Insuffisance cardiaque: amiodarone
Arythmie ventriculaire: amiodarone, érythromycine
La diarrhée: érythromycine
Diarrhée à Clostridium difficile: érythromycine
Pancréatite: érythromycine, simvastatine
Syndrome de Stevens-Johnson: amiodarone, érythromycine
Nécrolyse épidermique toxique: amiodarone, érythromycine
Hépatite cholestatique: érythromycine, simvastatine
Insuffisance hépatique: érythromycine, simvastatine
Réaction d'hypersensibilité: amiodarone
Réactions cutanées allergiques: érythromycine
Insuffisance rénale: amiodarone
Néphrite tubulo-interstitielle: érythromycine
Perte auditive: érythromycine
Rupture du tendon: simvastatine
Sur la base de vos
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Abstract: Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics. Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind. The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome. Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic. Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable. Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.
Abstract: Amiodarone is considered to be safe in patients with prior QT prolongation and torsades de pointes taking class I antiarrhythmic agents who require continued antiarrhythmic drug therapy. However, the safety of amiodarone in advanced heart failure patients with a history of drug-induced torsades de pointes, who may be more susceptible to proarrhythmia, is unknown. Therefore, the objective of this study was to assess amiodarone safety and efficacy in heart failure patients with prior antiarrhythmic drug-induced torsades de pointes. We determined the history of torsades de pointes in 205 patients with heart failure treated with amiodarone, and compared the risk of sudden death in patients with and without such a history. To evaluate the possibility that all patients with a history of torsades de pointes would be at high risk for sudden death regardless of amiodarone treatment, we compared this risk in patients with a history of torsades de pointes who were and were not subsequently treated with amiodarone. Of 205 patients with advanced heart failure, 8 (4%) treated with amiodarone had prior drug-induced torsades de pointes. Despite similar severity of heart failure, the 1-year actuarial sudden death risk was markedly increased in amiodarone patients with than without prior torsades de pointes (55% vs 15%, p = 0.0001). Similarly, the incidence of 1-year sudden death was markedly increased in patients with prior torsades de pointes taking amiodarone compared with such patients who were not subsequently treated with amiodarone (55% vs 0%, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Abstract: OBJECTIVE: To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. METHODS: A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg simvastatin was administered orally. Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours. RESULTS: Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum simvastatin concentration-time curve from time zero to 24 hours [AUC(0-24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of simvastatin acid 3.4-fold (p < 0.001) and the AUC(0-24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil. CONCLUSIONS: Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided. As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used.
Abstract: BACKGROUND: Simvastatin is a cholesterol-lowering agent that is metabolized through CYP3A4. We studied the effect of grapefruit juice on the pharmacokinetics of orally administered simvastatin. METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 60 mg simvastatin with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 and 1 1/2 hours after simvastatin administration. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and those of active (naive) and total (after hydrolysis) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by a radioenzyme inhibition assay. RESULTS: Grapefruit juice increased the mean peak serum concentration (Cmax) of unchanged simvastatin about 9-fold (range, 5.1-fold to 31.4-fold; P < .01) and the mean area under the serum simvastatin concentration-time curve [AUC(0-infinity)] 16-fold (range, 9.0-fold to 37.7-fold; P < .05). The mean Cmax and AUC(0-infinity) of simvastatin acid were both increased about 7-fold (P < .01). Grapefruit juice increased the mean AUC(0-infinity) of active and total HMG-CoA reductase inhibitors 2.4-fold (P < .01) and 3.6-fold (P < .01), respectively. The time of the peak concentration of active and total HMG-CoA reductase inhibitors was increased by grapefruit juice (P < .05). CONCLUSION: Grapefruit juice greatly increased serum concentrations of simvastatin and simvastatin acid and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors. The probable mechanism of this interaction was inhibition of CYP3A4-mediated first-pass metabolism of simvastatin by grapefruit juice in the small intestine. Concomitant use of grapefruit juice and simvastatin, at least in large amounts, should be avoided, or the dose of simvastatin should be greatly reduced.
Abstract: A novel human organic transporter, OATP2, has been identified that transports taurocholic acid, the adrenal androgen dehydroepiandrosterone sulfate, and thyroid hormone, as well as the hydroxymethylglutaryl-CoA reductase inhibitor, pravastatin. OATP2 is expressed exclusively in liver in contrast to all other known transporter subtypes that are found in both hepatic and nonhepatic tissues. OATP2 is considerably diverged from other family members, sharing only 42% sequence identity with the four other subtypes. Furthermore, unlike other subtypes, OATP2 did not transport digoxin or aldosterone. The rat isoform oatp1 was also shown to transport pravastatin, whereas other members of the OATP family, i.e. rat oatp2, human OATP, and the prostaglandin transporter, did not. Cis-inhibition studies indicate that both OATP2 and roatp1 also transport other statins including lovastatin, simvastatin, and atorvastatin. In summary, OATP2 is a novel organic anion transport protein that has overlapping but not identical substrate specificities with each of the other subtypes and, with its liver-specific expression, represents a functionally distinct OATP isoform. Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters suggests that they are responsible for the hepatic uptake of this liver-specific hydroxymethylglutaryl-CoA reductase inhibitor in rat and man.
Abstract: BACKGROUND: Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that is used as a cholesterol-lowering agent and is metabolized by cytochrome P450 3A (CYP3A) enzymes. Diltiazem is a substrate and an inhibitor of CYP3A enzymes and is commonly coadministered with cholesterol-lowering agents such as simvastatin. The objective of this study was to quantify the effect of diltiazem on the pharmacokinetics of simvastatin. METHOD: A fixed-order study was conducted in 10 healthy volunteers with a 2-week washout period between the phases. In one arm of the study, a single 20-mg dose of simvastatin was administered orally; the second arm entailed administration of a single 20-mg dose of simvastatin orally after 2 weeks of treatment with 120 mg diltiazem twice a day. RESULTS: Diltiazem significantly increased the mean peak serum concentration of simvastatin by 3.6-fold (P < .05) and simvastatin acid by 3.7-fold (P < .05). Diltiazem also significantly increased the area under the serum concentration-time curve of simvastatin 5-fold (P < .05) and the elimination half-life 2.3-fold (P < .05). There was no change in the time to peak concentration for simvastatin and simvastatin acid. CONCLUSION: Diltiazem coadministration resulted in a significant interaction with simvastatin, probably by inhibiting CYP3A-mediated metabolism. Concomitant use of diltiazem or other potent inhibitors of CYP3A with simvastatin should be avoided, or close clinical monitoring should be used.
Abstract: BACKGROUND: Concomitant treatment with simvastatin and gemfibrozil, two lipid-lowering drugs, has been associated with occurrence of myopathy in case reports. The aim of this study was to determine whether gemfibrozil affects the pharmacokinetics of simvastatin and whether it affects CYP3A4 activity in vitro. METHODS: A double-blind, randomized crossover study with two phases (placebo and gemfibrozil) was carried out. Ten healthy volunteers were given gemfibrozil (600 mg twice daily) or placebo orally for 3 days. On day 3 they ingested a single 40-mg dose of simvastatin. Plasma concentrations of simvastatin and simvastatin acid were measured up to 12 hours. In addition, the effect of gemfibrozil (0 to 1,200 micromol/L) on midazolam 1'-hydroxylation, a CYP3A4 model reaction, was investigated in human liver microsomes in vitro. RESULTS: Gemfibrozil increased the mean total area under the plasma concentration-time curve of simvastatin [AUC(0-infinity)] by 35% (P < .01) and the AUC(0-infinity) of simvastatin acid by 185% (P < .001). The elimination half-life of simvastatin was increased by 74% (P < .05), and that of simvastatin acid was increased by 51% (P < .01) by gemfibrozil. The peak concentration of simvastatin acid was increased by 112%, from 3.20 +/- 2.73 ng/mL to 6.78 +/- 4.67 ng/mL (mean +/- SD; P < .01). In vitro, gemfibrozil showed no inhibition of midazolam 1'-hydroxylation. CONCLUSIONS: Gemfibrozil increases plasma concentrations of simvastatin and, in particular, its active form, simvastatin acid, suggesting that the increased risk of myopathy in combination treatment is, at least partially, of a pharmacokinetic origin. Because gemfibrozil does not inhibit CYP3A4 in vitro, the mechanism of the pharmacokinetic interaction is probably inhibition of non-CYP3A4-mediated metabolism of simvastatin acid.
Abstract: BACKGROUND: Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol-lowering drug simvastatin has an extensive first-pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of simvastatin. METHODS: In a randomized cross-over study with two phases and a washout of 4 weeks, 10 healthy volunteers received a 5-day pretreatment with rifampin (600 mg daily) or placebo. On day 6, a single 40-mg dose of simvastatin was administered orally. Plasma concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 12 hours with a sensitive liquid chromatography-ion spray tandem mass spectrometry method. RESULTS: Rifampin decreased the total area under the plasma concentration-time curve of simvastatin and simvastatin acid by 87% (P < .001) and 93% (P < .001), respectively. Also the peak concentrations of both simvastatin and simvastatin acid were reduced greatly (by 90%) by rifampin (P < .001). On the other hand, rifampin had no significant effect on the elimination half-life of simvastatin or simvastatin acid. CONCLUSIONS: Rifampin greatly decreases the plasma concentrations of simvastatin and simvastatin acid. Because the elimination half-life of simvastatin was not affected by rifampin, induction of the CYP3A4-mediated first-pass metabolism of simvastatin in the intestine and the liver probably explains this interaction. Concomitant use of potent inducers of CYP3A4 can lead to a considerably reduced cholesterol-lowering efficacy of simvastatin.
Abstract: OBJECTIVE: The aim of this study was to examine the effect of carbamazepine on the pharmacokinetics of orally administered simvastatin in healthy volunteers. METHODS: In a randomised, two-phase crossover study and a wash out of 2 weeks, 12 healthy volunteers took carbamazepine for 14 days (600 mg daily except 200 mg daily for the first 2 days) or no drug. On day 15, each subject ingested 80 mg simvastatin. Serum concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 24 h. RESULTS: Carbamazepine decreased the mean total area under the serum concentration-time curve of simvastatin and simvastatin acid by 75% ( P<0.001) and 82% ( P<0.001), respectively. The mean peak concentrations of both simvastatin and simvastatin acid were reduced by 68% ( P<0.01), and half-life of simvastatin acid was shortened from 5.9+/-0.3 h to 3.7+/-0.5 h ( P<0.01) by carbamazepine. CONCLUSION: Carbamazepine greatly reduces the serum concentrations of simvastatin and simvastatin acid, probably by inducing their metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided or the dose of simvastatin should be considerably increased.
Abstract: The aim of this pharmacokinetic evaluation was to show the effect of the extra methyl group in simvastatin on esterase hydrolysis between lovastatin and simvastatin in male and female volunteers. This study was based on the plasma concentration-time curves and the pharmacokinetics of lovastatin and simvastatin with its respective active metabolite statin-beta-hydroxy acid obtained from two different bioequivalence studies, each with 18 females and 18 males. Results were: The group of female volunteers showed a higher yield of the active metabolite beta-hydroxy acid than the group of males (p < 0.002) for both lovastatin and simvastatin. This difference was not related to the body weight of both groups. In the male/female groups, subject-dependent yield of active metabolite beta-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of data points when the AUCt lovastatin was plotted vs. that of the beta-hydroxy acid metabolite. In the fan of data points, subgroups could be distinguished, each showing a different regression line and with a different Y-intercept (AUCtbeta-hydroxy acid). Lovastatin hydrolysis was higher than simvastatin hydrolysis. It was possible to discriminate between hydrolysis of both lovastatin and simvastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing different but high yield of statin beta-hydroxy acid can be explained by variable hydrolysis of plasma and hepatic microsomal and cytosolic carboxyesterase activity. This study showed clearly that despite the subject-dependent hydrolysis of lovastatin/simvastatin to the active metabolite, males tend to hydrolyse less than females. The extra methyl group in simvastatin results in less hydrolysis due to steric hindrance.
Abstract: PURPOSE: In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin (SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug interactions. METHODS: P-gp mediated efflux of SV, SVA, and AVA was determined by directional transport across monolayers of LLC-PK1 cells and LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50 microM. RESULTS: Directional transport studies showed insignificant P-gp mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA, respectively. Inhibition studies did not show the same trend as the transport studies with SV and AVA inhibiting P-gp (IC50 -25-50 microM) but SVA not showing any inhibition of P-gp. CONCLUSIONS: The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.
Abstract: Statins are the treatment of choice for the management of hypercholesterolaemia because of their proven efficacy and safety profile. They also have an increasing role in managing cardiovascular risk in patients with relatively normal levels of plasma cholesterol. Although all statins share a common mechanism of action, they differ in terms of their chemical structures, pharmacokinetic profiles, and lipid-modifying efficacy. The chemical structures of statins govern their water solubility, which in turn influences their absorption, distribution, metabolism and excretion. Lovastatin, pravastatin and simvastatin are derived from fungal metabolites and have elimination half-lives of 1-3 h. Atorvastatin, cerivastatin (withdrawn from clinical use in 2001), fluvastatin, pitavastatin and rosuvastatin are fully synthetic compounds, with elimination half-lives ranging from 1 h for fluvastatin to 19 h for rosuvastatin. Atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and pitavastatin are relatively lipophilic compounds. Lipophilic statins are more susceptible to metabolism by the cytochrome P(450) system, except for pitavastatin, which undergoes limited metabolism via this pathway. Pravastatin and rosuvastatin are relatively hydrophilic and not significantly metabolized by cytochrome P(450) enzymes. All statins are selective for effect in the liver, largely because of efficient first-pass uptake; passive diffusion through hepatocyte cell membranes is primarily responsible for hepatic uptake of lipophilic statins, while hydrophilic agents are taken up by active carrier-mediated processes. Pravastatin and rosuvastatin show greater hepatoselectivity than lipophilic agents, as well as a reduced potential for uptake by peripheral cells. The bioavailability of the statins differs greatly, from 5% for lovastatin and simvastatin to 60% or greater for cerivastatin and pitavastatin. Clinical studies have demonstrated rosuvastatin to be the most effective for reducing low-density lipoprotein cholesterol, followed by atorvastatin, simvastatin and pravastatin. As a class, statins are generally well tolerated and serious adverse events, including muscle toxicity leading to rhabdomyolysis, are rare. Consideration of the differences between the statins helps to provide a rational basis for their use in clinical practice.
Abstract: Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
Abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: BACKGROUND: The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death. METHOD: Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017. RESULTS: Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated. CONCLUSION: ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.
Abstract: Amiodarone is one of the most commonly used antiarrhythmic drugs. Despite its well-known side effects, amiodarone is considered to be a relatively safe drug, especially in short-term usage to prevent life-threatening ventricular arrhythmias. Our case demonstrates an instance where short-term usage can yield drug side effect.