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T Colombo, M Zucchetti and M D'Incalci
Laboratory of Cancer Chemotherapy, Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.
Cyclosporin A (CsA) inhibits the membrane transport protein Pgp and can thus restore sensitivity to doxorubicin (Dx) and other antineoplastic agents in multidrug resistant cancer cells. Because Pgp is not expressed only in resistant tumor cells but also in normal tissues, CsA may modify the distribution of a concomitantly given antitumor agent which is a substrate for Pgp-mediated transport. We investigated Dx distribution in rats and mice injected i.p. with CsA then 30 min later with an i.v. dose of Dx. In both species CsA treatment markedly increased Dx concentrations in liver, adrenals and kidney, with a small but significant increase in the heart and no change in brain. The CsA- induced changes in Dx tissue levels were not related to inhibition of Dx metabolism or reduced fecal and renal Dx elimination. A marked delayed lethal toxicity of Dx was seen in mice treated with CsA and Dx but not with either drug alone. These results indicate that CsA can profoundly alter Dx pharmacokinetics and toxicity and suggest that caution is advisable when prescribing this combination to cancer patients using full Dx doses.
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