Pharmacokinetics of amiodarone after intravenous and oral administration

Andreasen, F.; Agerbæk, H.; Bjerregaard, Preben; Gøtzsche, H

doi:10.1007/bf00562807

Cited by 165 publications

(59 citation statements)

References 5 publications

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“…Elevated serum concentrations have also been reported in patients treated by amiodarone for cardiac arrhythmias. Andreasen et al (1981) obtained a mean plasma concentration of 1.7,M after daily oral administration of 200 mg, reaching 14.6 pM after an i.v. injection of 400 mg. Mostow et al (1984) reported that serum concentration averaged 6.4 pM during the loading phase of an i.v.…”

Section: Methodsmentioning

confidence: 89%

Amiodarone is more efficient than verapamil in reversing resistance to anthracyclines in tumour cells

Chauffert

Rey²,

Coudert³

et al. 1987

Br J Cancer

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Summary We have previously demonstrated that amiodarone is able to reverse resistance of rat colon cancer cells to anthracyclines. We now compare the efficiency of amiodarone to verapamil one, another antiarrhythmic agent used in experimental systems and in clinical trials to enhance the effects of anthracyclines on resistant cancer cells. Amiodarone is more efficient than verapamil when both drugs are used at the same molar concentrations. Desethylamiodarone, the main metabolite of amiodarone, is as efficient as its precursor. Optimal concentrations of amiodarone are obtained without side effects in the sera of patients treated by oral administration followed by a loading infusion of amiodarone. On the other hand, maximal tolerated levels of verapamil reported in clinical trials are less efficient than amiodarone maximal levels in the reversal of resistance to anthracyclines in our experimental model in vitro. We suggest that amiodarone, which is more efficient and less toxic than verapamil, could be substituted for verapamil in future clinical trials.In many experimental tumours, including rat colon cancer, resistance to anthracyclines is partly attributed to an energydependent efflux of the drugs from the cancer cells (Skovsgaard, 1975;Inaba et al., 1979). Tsuruo et al. (1982) first demonstrated that verapamil was able to inhibit this efflux, so restoring sensitivity to anthracyclines of resistant cancer cells. We previously reported that amiodarone, a relatively non toxic antiarrhythmic agent, was able to restore sensitivity to anthracyclines in naturally resistant rat colon cancer cells (Chauffert et al., 1986). In the present study, we demonstrate that amiodarone is more efficient than verapamil in enhancing the cytotoxic effect of 4'-deoxydoxorubicin on rat colon cancer cells. We also demonstrate that the effect of amiodarone on cancer cells is long-lasting and that efficient plasma concentrations of amiodarone can be reached in cancer patients without appreciable toxicity. Materials and methodsCells and culture conditions DHD/K12/PRO cell line was established in our laboratory from a transplantable colon adenocarcinoma induced by 1,2-dimethylhydrazine in syngeneic BDIX rats (Martin et al., 1975). DHD/K12/PRO cells exhibit a primary resistance to anthracyclines due to an active drug efflux (Chauffert et al., 1984 Patient sera and amiodarone determinations Sera were obtained from 3 patients included in a clinical trial associating amiodarone and anthracyclines for the treatment of advanced colorectal cancer. Blood samples were collected after a period of at least 15 days during which the patients received an oral administration of 400mg amiodarone daily. The samples were collected before and at the end of a 3 h infusion of 450mg amiodarone diluted in 250ml of 50gl-1 dextrose solution. Concentrations of amiodarone and its main metabolite, desethylamiodarone, were determined according to Pourbaix et al. (1985). Briefly, serum was extracted twice in a mixture of phosphate buffer (pH 5.4) and n-hexane in the p...

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Section: Methodsmentioning

confidence: 89%

Amiodarone is more efficient than verapamil in reversing resistance to anthracyclines in tumour cells

Chauffert

Rey²,

Coudert³

et al. 1987

Br J Cancer

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“…Binding to normal plasma Classical methods Attempts to measure the protein binding of amiodarone by equilibrium dialysis and ultrafiltration were not successful, as other workers have found (Andreason et al, 1981;Neyroz & Bonati, 1985). Even after dialysis for 24 h, the radioactivity on the buffer side of the cell was no greater than the background level, while there was a 30% loss of counts from the plasma.…”

Section: Resultsmentioning

confidence: 99%

“…Loss of drug to the ultrafiltration apparatus generally invalidates the use of this method to study protein binding. Andreason et al (1981) were also unsuccessful with a variation of the technique in which plasma was filtered under pressure through a cellophane membrane. Amiodarone is extremely hydrophobic in both the neutral and charged forms (Chatelain & Laruel, 1985), and this is probably why so little crosses dialysis membranes, even when the nominal MW cutoff is for much larger molecules.…”

Section: Resultsmentioning

confidence: 99%

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

Veronese

McLean

Hendriks

1988

Brit J Clinical Pharma

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“…1 It is incompletely absorbed (35% to 65%) after oral administration. [2][3][4] It is taken up very extensively by tissue, with marked interindividual variation. 5 Estimates of the elimination halflife of amiodarone vary, depending on how it has been measured.…”

Section: Pharmacokineticsmentioning

confidence: 99%