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Differences in accumulation of anthracyclines daunorubicin, doxorubicin and epirubicin in rat tissues revealed by immunocytochemistry

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Abstract

Although anthracycline antibiotics daunorubicin (DR), doxorubicin (DX), and epirubicin (ER) possess minor differences in their chemical structures, large differences are noted in their clinical use, as well as in cellular and plasma pharmacokinetic parameters in vivo. Immunocytochemistry for DR, DX, or ER was developed using an anti-DR monoclonal antibody (ADM-1-11), which has been demonstrated to react equally well with each of the three drugs, and therefore it was used for comparing their accumulation in several rat tissue cells after a single i.v. injection of each drug. In the kidney, immunoreactivity for each drug was distributed in essentially the same pattern and in the same strength 2 h after injection, but quite differently distributed in kidney cells thereafter, so that at 120-h post-injection significant amounts of DX and ER remained, but DR had almost completely vanished. Similar patterns of accumulation were observed in cells of other tissues including the pancreas, hair follicle, and stomach, with the exception of the intestine in which none of the three drugs remained after 120 h. These results appear to be supported by previous pharmacokinetic studies on the anthracyclines. The mechanism for such differences among the three drugs remains obscure, but the hydroxyl group at C-14 of DX and ER molecule might be related to the strong propensity of DX and ER to accumulate in tissue cells. The present results should contribute to the understanding of the mechanisms of the differences in the pharmacokinetics, as well as the possibly in anti-tumor activities of the anthracyclines.

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Fig. 1
Fig. 2

Abbreviations

DR:

Daunorubicin

DX:

Doxorubicin

ER:

Epirubicin

ICC:

Immunocytochemistry

GA:

Glutaraldehyde

PBS:

Phosphate-buffered saline

Pgp:

P-glycoprotein

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Acknowledgments

We are grateful to C. Narahara, M. Kawaguchi and K. Nagaoka for their technical assistance throughout this study. This study was supported in part by a grant the Japanese Society for the Promotion of Science (15590148). 606.

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Authors and Affiliations

  1. Department of Applied Life Science, Faculty of Biotechnology and Life Science, Sojo University, Ikeda 4-22-1, Kumamoto, 860-0082, Japan

    Masashi Shin, Hayato Matsunaga & Kunio Fujiwara

Authors
  1. Masashi Shin
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  2. Hayato Matsunaga
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  3. Kunio Fujiwara
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Corresponding author

Correspondence to Kunio Fujiwara.

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Supplementary Figure 1 (TIFF 60 kb)

418_2010_700_MOESM2_ESM.tif

Supplementary Figure 2 Immunostaining for DR, DX or ER in the kidney cortex of rats 2 h after a single i.v. injection of each drug (15 mg/kg; a to d) DR (a, b), DX (c), ER (d). a Lower magnification of the renal cortex. Protease digestion step was omitted in DR ICC. Immunostaining was absent in the S1 and S2 segments of the proximal tubules, but present weakly in S3 segment as well as in the distal convolution cells. b Cortex. Sections were pre-digested with 0.004% protease at 30 °C for 1 h prior to immunoreaction. Note weak or moderate staining in the microvilli (arrowheads), in the nuclei (arrows) of the S1 and S2 segment cells, and strong staining in distal convolution cells. c, d Cortex. Sections were pre-digested with 0.004% protease at 30 °C for 2 h prior to immunoreaction. Note that immunostaining patterns as well as intensity of immunostaining were both very comparable to those of Fig. 1b in the text. G, glomerulus; P, proximal tubule; D, distal tubule a = 100 μm; b, c, d = 20 μm (TIFF 638 kb)

Supplementary Table 1 (DOC 39 kb)

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Shin, M., Matsunaga, H. & Fujiwara, K. Differences in accumulation of anthracyclines daunorubicin, doxorubicin and epirubicin in rat tissues revealed by immunocytochemistry. Histochem Cell Biol 133, 677–682 (2010). https://doi.org/10.1007/s00418-010-0700-3

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