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Pharmacokinetics of 4'-Deoxy-4'-iodo-doxorubicin in Plasma and Tissues of Tumor-bearing Mice Compared with Doxorubicin¹

Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan [F. F., R. C.]; and Farmitalia-Carlo Erba, Via Imbonati 24, 20158 Milan [C. P.], Italy

It has been reported that 4'-deoxy-4'-iodo-doxorubicin (4'-deoxy-4'-I-DX) displays, on experimental tumors, a spectrum of activity comparable to that of doxorubicin, is active when administered orally, is not cardiotoxic, and is cytotoxic to doxorubicin-resistant cells. We have investigated by high-performance liquid chromatography the pharmacokinetics of this drug in comparison with doxorubicin by treating mice bearing colon 38 adenocarcinoma with equal doses of the two drugs i.v. 4'-Deoxy-4'-I-DX, unlike doxorubicin, is transformed into several metabolites. The 13-dihydro derivative is the major metabolite found; in tumor and in all the organs it accounts for 4–7% of the total fluorescent area under the curve, whereas in plasma and liver it accounts for 15 and 34%, respectively. 4'-Deoxy-4'-I-DX disappears from plasma with a terminal half-life of 5 h, which is half the terminal half-life of doxorubicin (11 h), and its efficiency of absorption after oral administration is 27%. Tissue concentrations of 4'-deoxy-4'-I-DX are initially highest in lung and spleen, whereas those of doxorubicin are highest in liver and kidney. 4'-Deoxy-4'-I-DX levels are higher than those of doxorubicin in tumor, spleen, lung, small intestine, brain, pancreas, and ovaries whereas they are similar in heart, liver, kidney, and bone marrow. The rate of elimination of the new analogue is higher than that of doxorubicin from the tumor and all the organs investigated except the liver. The area under the curve of 4'-deoxy-4'-I-DX is similar to that of doxorubicin in tumor and spleen, whereas it is three times lower in heart. This may explain the lack of cardiotoxicity of this new analogue, which is equiactive and equitoxic with doxorubicin on the experimental system tested.

¹ This work was supported by Grant 84.00855.44 of the Finalized Project "Oncologia" of the Consiglio Nazionale delle Ricerche, Rome, Italy.

² To whom requests for reprints should be addressed.

Received 4/14/87. Accepted 6/22/87.

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