Plasma protein binding of amiodarone in a patient population: measurement by erythrocyte partitioning and a novel glass‐binding method.

Veronese, Maurice E.; McLean, Stuart; Hendriks, R.

doi:10.1111/j.1365-2125.1988.tb05311.x

Cited by 29 publications

(18 citation statements)

References 27 publications

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“…The amiodarone concentration required to trigger phosphatidylserine exposure is in the range of concentrations encountered during chronic therapy [45]. However, considering the strong protein binding of amiodarone [46,47], the free plasma concentration may be lower during therapeutic dosages. Thus, the present observations may not be relevant for the side effects of the drug at subtoxic concentrations.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Erythrocyte Cell Membrane Scrambling by Amiodarone

Jacobi

Lang²,

Bissinger³

et al. 2007

Cell Physiol Biochem

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Side effects of amiodarone, an effective antiarrhythmic drug, include anemia, which may be caused by decreased formation or accelerated death of erythrocytes. Suicidal erythrocyte death (eryptosis) is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Stimulators of erythrocyte membrane scrambling include increase of cytosolic Ca²⁺ concentration ([Ca²⁺]i) following activation of Ca²⁺-permeable cation channels. Moreover, eryptosis is triggered by ceramide. The present study has been performed to test for an effect of amiodarone on eryptosis. Erythrocytes from healthy volunteers were exposed to amiodarone and phosphatidylserine exposure (annexin V binding), cell volume (forward scatter), [Ca²⁺]i (Fluo3-dependent fluorescence), and ceramide formation (anti-ceramide-FITC antibody and radioactive labelling) determined by flow cytometry. Exposure of erythrocytes to amiodarone (1 μM) increased [Ca²⁺]i and triggered annexin V binding, but did not significantly decrease forward scatter and did not significantly influence ceramide formation. Amiodarone augmented the increase of annexin binding following hypertonic shock (addition of 550 mM sucrose) but did not significantly alter the enhanced annexin binding following Cl^- removal (replacement with gluconate). Amiodarone did not significantly modify the decrease of forward scatter following hypertonic shock or Cl^- removal. The present observations disclose a novel action of amiodarone which may contribute to the side effects of the drug.

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Section: Discussionmentioning

confidence: 99%

Stimulation of Erythrocyte Cell Membrane Scrambling by Amiodarone

Jacobi

Lang²,

Bissinger³

et al. 2007

Cell Physiol Biochem

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“…Its free fraction is independent of the total drug concentration and albumin level, indicating that the binding is not concentration dependent over the normal therapeutic range 6 . There is some evidence that DEA is less lipid soluble than the parent compound and is somewhat less protein-bound 7 .…”

Section: Pharmacokineticsmentioning

confidence: 92%

Therapeutic monitoring of amiodarone: pharmacokinetics and evaluation of the relationship between effect and dose/concentration

Vyskocilova¹,

Grundmann²,

Kacířová³

2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Amiodarone is the most effective agent in the therapy of arrhythmias. However, the clinical effect of acute and chronic treatment is unclear and there are differences irrespective of comparable plasma/myocardial amiodarone and its metabolite desethylamiodarone concentations as well. Its unusual pharmacokinetics results in interindividual variation in plasma levels. The association between amiodarone and desethylamiodarone plasma levels and clinical efficacy is difficult to evaluate. This review was carried out to assess whether there is any objective correlation between amiodarone and desethylamiodarone plasma levels and the clinical effect. We summarized the results of relevant studies and clarified the relationship between plasma levels and effect vis á vis the pharmacokinetics and pharmacogenetics of this drug. Certain correlation was seen with oral amiodarone therapy, in others, plasma amiodarone levels were unrelated to therapeutic response and showed no correlation with changes in electrocardiogram or electrophysiological parametres. Several studies show that plasma concentration ranging between 0.5 and 2.5 mg/L appears to be the most effective, others demonstrate no difference between responders and non-responders. One way of interpreting plasma levels is to establish an individual patient´s effective concentration. Therapeutic drug monitoring can contribute to determining optimal concentration.

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“…On the other hand, it was reported that the plasma protein binding of amiodarone was marked at 99.977%. 17) Thus, to clarify the possible effect of amiodarone on the protein binding of carvedilol in the reaction mixture, we conducted the same experiments in the absence of BSA (Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

<i>In Vitro</i> Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin

Sekimoto

Takamori

Nakamura

et al. 2016

Biological & Pharmaceutical Bulletin

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Carvedilol is mainly metabolized in the liver to O-glucuronide (O-Glu). We previously found that the glucuronidation activity of racemic carvedilol in pooled human liver microsomes (HLM) was increased, R-selectively, in the presence of amiodarone. The aim of this study was to clarify the mechanisms for the enhancing effect of amiodarone on R-and S-carvedilol glucuronidation. We evaluated O-Glu formation of R-and S-carvedilol enantiomers in a reaction mixture of HLM including 0.2% bovine serum albumin (BSA). In the absence of amiodarone, glucuronidation activity of R-and S-carvedilol for 25 min was 0.026, and 0.51 pmol/min/mg protein, and that was increased by 6.15 and 1.60-fold in the presence of 50 µM amiodarone, respectively. On the other hand, in the absence of BSA, or when BSA was replaced with human serum albumin, no enhancing effect of amiodarone on glucuronidation activity was observed, suggesting that BSA played a role in the mechanisms for the enhancement of glucuronidation activity. Unbound fraction of S-carvedilol in the reaction mixture was greater than that of R-carvedilol in the absence of amiodarone. Also, the addition of amiodarone caused a greater increase of unbound fraction of R-carvedilol than that of S-carvedilol. These results suggest that the altered protein binding by amiodarone is a key mechanism for R-selective stimulation of carvedilol glucuronidation.Key words drug interaction; protein binding; human liver microsome; glucuronidation; carvedilol; amiodaroneThe nonselective β-and α 1 -adrenoceptor antagonist carvedilol has been clinically used to treat chronic heart failure, as well as hypertension, angina pectoris, and cardiac arrhythmia.1) Carvedilol is administered orally as a racemate mixture, but undergoes enantioselective first-pass metabolism. The blood concentration of the S-enantiomer, which has high β-blocking activity, is approximately one-half of that of the R-enantiomer, which has low β-blocking activity.2,3) Both enantiomers are mostly eliminated by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.4) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.5) We previously demonstrated that R-carvedilol is metabolized mainly by CYP 2D6 and partly by CYP1A2, 2C9, and 3A4, and that S-carvedilol is metabolized mainly by CYP1A2 and partly by CYP2C9, 2D6, and 3A4.6-9) On the other hand, Ohno et al. found that uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol using microsomes from insect cells expressing human UGT. 10) They also reported that glucuronidation of R-carvedilol is mediated by UGT1A1 and 2B4, and glucuronidation of S-carvedilol is mediated by UGT2B7 and 2B4. 10) In 2005, Fukumoto et al. reported that coadministration of amiodarone affects the enantioselective pharmacokinetics of carvedilol in patients with heart failure. 11) That is, the mean serum concentration to dose (C/D...

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Plasma protein binding of amiodarone in a patient population: measurement by erythrocyte partitioning and a novel glass‐binding method.

Cited by 29 publications

References 27 publications

Stimulation of Erythrocyte Cell Membrane Scrambling by Amiodarone

Stimulation of Erythrocyte Cell Membrane Scrambling by Amiodarone

Therapeutic monitoring of amiodarone: pharmacokinetics and evaluation of the relationship between effect and dose/concentration

<i>In Vitro</i> Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin

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