Influence of Pharmacokinetic Variations on the Pharmacological Properties of Adriamycin

Arena, Elena; D’Alessandro, Natale; Dusonchet, Luisa; Gebbia, Nicola; Gerbasi, F.; Sanguedolce, R; Rausa, L

doi:10.1007/978-3-642-95227-2_11

Cited by 19 publications

(16 citation statements)

References 10 publications

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“…The plasma concentration decay curve of adriamycin in the rat was similar to that in man and to that obtained in the rat by other workers (Arena, d'Alessandro, Dusonchet, Gebbia, Gerbasi, Palazzoadriano, Raineri, Ransa & Tubaro, 1971;Yesair et al, 1972). Thus, a two compartment system was again postulated and the predicted plasma concentrations lay within one standard error of the observed values.…”

Section: Discussionsupporting

confidence: 87%

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The Persistence of Adriamycin in Man and Rat

Wilkinson

Mawer

1974

Brit J Clinical Pharma

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Adriamycin was administered as a single intravenous dose. The plasma concentration in man and rat decayed as a double exponential function of time. A two compartment model was used to predict plasma and tissue concentrations in man and the rat. The validity of the tissue concentration predictions was confirmed experimentally in the rat. Tissue components had a high capacity for the drug. There was evidence in the rat of preferential accumulation in the liver, spleen and bone marrow. The large tissue capacity and the prolonged half time for elimination predispose to accumulation. This may be responsible for the greater toxicity of treatment schedules with short intervals between consecutive doses.

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Section: Discussionsupporting

confidence: 87%

“…The persistence of the drug in these tissiXes has been noted by other workers (Arena et al, 1971;di Fronzo, Gambetta & Lenaz, 1971) and may be due to preferential uptake of adriamycin by the reticuloendothelial system. This may be of therapeutic importance if the phenomenon also occurs in the neoplastic reticular cell.…”

Section: Discussionsupporting

confidence: 66%

The Persistence of Adriamycin in Man and Rat

Wilkinson

Mawer

1974

Brit J Clinical Pharma

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“…Therefore, we propose that the mitochondrial deformations which are among the earliest signs of the development of cardiomyopathy during adriamycin therapy [7][8][9], are the consequence of the strong and specific interaction of the drug with inner mitochondrial membrane cardiolipin.…”

Section: Discussionmentioning

confidence: 99%

“…6). The early development of cardiac failure is characterized by changes in the morphology and function of heart mitochondria [7][8][9]. Moreover, the development of ECG changes shows a good correlation with the impairment of mitochondrial function [8].…”

Section: Introductionmentioning

confidence: 99%

The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes

Nicolay

Timmers

Spoelstra

et al. 1984

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The interaction of adriamycin with cardiolipin in model membranes and in various membrane preparations derived from rat liver mitochondria was studied and the results are analyzed in the light of a possible specific interaction between adriamycin and cardiolipin. It was found that adriamycin binds to cardiolipin-containing model membranes with a fixed stoichiometry of two drug molecules per cardiolipin. Furthermore, the extent of drug complexation by mitochondria and mitoplasts (inner membrane plus matrix) is in reasonable agreement with their cardiolipin content. In contrast, adriamycin-binding curves of inner membrane ghosts and submitochondrial particles reveal considerable association to an additional site, presumably RNA. The evidence for the potential importance of RNA as a target comes from experiments on outer membranes and microsomes which both appear to bind substantial amounts of adriamycin. Removal of the major part of the RNA associated with these fractions by EDTA treatment is accompanied by a dramatic reduction of binding capacity. We propose that endogenous RNA present in mitochondria and mitoplasts is not accessible for adriamycin at low concentrations of the drug due to the presence of an intact lipid barrier. This potential site comes to expression in ghosts and submitochondriai particles, due to the absence of an intact lipid bilayer and due to the inside-out orientation of the limiting membrane, respectively. Electron microscopical studies show that adriamycin induces dramatic changes in mitochondrial morphology, similar to the uncoupler-induced effects described by Knoll and Brdiczka (Biochim. Biophys. Acta 733, 102-110 (1983)). Adriamycin has an uncoupling effect on mitochondrial respiration and oxidative phosphorylation. The concentration dependence of this effect correlates with the adriamycin-binding curve for mitochondria which implies that only bound adriamycin actively inhibits respiration.

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“…Digoxin thus inhibits adriamycin uptake acutely in the in vitro Langendoff heart preparation. This observation combined with the initial work of Arena et al (1972) …”

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confidence: 64%