Summary
To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(–/–) and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg–1. Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration–time curve of doxorubicin in mdr1a(–/–) mice were 1.6- and 1.2-fold higher respectively. The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(–/–) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(–/–) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of doxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(–/–) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Bartlett, N. L., Lum, B. L., Fisher, G. A., Brophy, N. A., Ehsan, M. N., Halsey, J. & Sikic, B. I. (1994). Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance. J Clin Oncol 12: 835–842.
Bellamy, W. T., Peng, Y. M., Odeleye, A., Ellsworth, L., Xu, M. J., Grogan, T. M. & Weinstein, R. S. (1995). Cardiotoxicity in the SCID mouse following administration of doxorubicin and cyclosporin A. Anti-Cancer Drugs 6: 736–743.
Colombo, T., Zucchetti, M. & D'Incalci, M. (1994). Cyclosporin A markedly changes the distribution of doxorubicin in mice and rats. J Pharmacol Exp Ther 269: 22–27.
Cordon-Cardo, C., O'Brien, J. P., Casals, D., Rittman-Grauer, L., Biedler, J. L., Melamed, M. R. & Bertino, J. R. (1989). Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites. Proc Natl Acad Sci USA 86: 695–698.
Croop, J. M., Raymond, M., Haber, D., Devault, A., Arceci, R. J., Gros, P. & Housman, D. E. (1989). The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol 9: 1346–1350.
Dantzig, A. H., Shepard, R. L., Cao, J., Law, K. L., Ehlhardt, W. J., Baughman, T. M., Bumol, T. F. & Starling, J. J. (1996). Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res 56: 4171–4179.
De Jong, J., Schoofs, P. R., Snabilié, A. M., Bast, A. & van der Vijgh, W. J. F. (1993). The role of biotransformation in anthracycline-induced cardiotoxicity in mice. J Pharmacol Exp Ther 266: 1312–1320.
Endicott, J. A. & Ling, V. (1989). The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58: 137–171.
Erlichman, C., Moore, M., Thiessen, J. J., Kerr, I. G., Walker, S., Goodman, P., Bjarnason, G., DeAngelis, C. & Bunting, P. (1993). Phase I pharmacokinetic study of cyclosporin A combined with doxorubicin. Cancer Res 53: 4837–4842.
Giaccone, G., Linn, S. C., Welink, J., Catimel, G., Stieltjes, H., van der Vijgh, W. J. F., Eeltink, C., Vermorken, J. B. & Pinedo, H. M. (1997). A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors. Clin Cancer Res 3: 2005–2015.
Gonzalez, O., Colombo, T., De Fusco, M., Imperatori, L., Zucchetti, M. & D'Incalci, M. (1995). Changes in doxorubicin distribution and toxicity in mice pretreated with the cyclosporin analogue SDZ PSC 833. Cancer Chemother Pharmacol 36: 335–340.
Hyafil, F., Vergely, C., du Vignaud, P. & Grand-Perret, T. (1993). In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res 53: 4595–4602.
Mayer, U., Wagenaar, E., Beijnen, J. H., Smit, J. W., Meijer, D. K. F., van Asperen, J., Borst, P. & Schinkel, A. H. (1996). Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by mdr1a P-glycoprotein. Br J Pharmacol 119: 1038–1044.
Mayer, U., Wagenaar, E., Dorobek, B., Beijnen, J. H., Borst, P. & Schinkel, A. H. (1997). Full blockade of intestinal P-glycoprotein and extensive inhibition of blood–brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 100: 2430–2436.
Mross, K., Maessen, P., van der Vijgh, W. J. F., Gall, H., Boven, E. & Pinedo, H. M. (1988). Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 6: 517–526.
Olson, R. D., Mushlin, P. S., Brenner, D. E., Fleischer, S., Cusack, B. J., Chang, B. K. & Boucek, R. J. (1988). Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci USA 85: 3585–3589.
Schinkel, A. H., Smit, J. J. M., van Tellingen, O., Beijnen, J. H., Wagenaar, E., van Deemter, L., Mol, CAAM, van der Valk, M. A., Robanus-Maandag, E. C., te Riele, H. P. J., Berns, A. J. M. & Borst, P. (1994). Disruption of the mousemdr1aP-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77: 491–502.
Schinkel, A. H., Wagenaar, E., van Deemter, L., Mol, CAAM & Borst, P. (1995). Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 96: 1698–1705.
Schinkel, A. H., Wagenaar, E., Mol, CAAM & van Deemter, L. (1996). P-glycoprotein in blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97: 2517–2524.
Schinkel, A. H., Mayer, U., Wagenaar, E., Mol, CAAM, van Deemter, L., Smit, J. J. M., van der Valk, M. A., Voordouw, A. C., Spits, H., van Tellingen, O., Zijlmans, JMJM, Fibbe, W. E. & Borst, P. (1997). Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 94: 4028–4033.
Sparreboom, A., van Asperen, J., Mayer, U., Schinkel, A. H., Smit, J. W., Meijer, D. K. F., Borst, P., Nooijen, W. J., Beijnen, J. H. & van Tellingen, O. (1997). Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94: 2031–2035.
Tang-Wai, D. F., Kajiji, S., DiCapua, F., de Graaf, D., Roninson, I. B. & Gros, P. (1995). Human (MDR1) and mouse (mdr1, mdr3) P-glycoproteins can be distinguished by their respective drug resistance profiles and sensitivity to modulators. Biochemistry 34: 32–39.
Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I. & Willingham, M. C. (1987). Cellular localization of the multidrug resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84: 7735–7738.
Tsuruo, T., Iida, H., Tsukagoshi, S. & Sakurai, Y. (1981). Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41: 1967–1972.
Van Asperen, J., Schinkel, A. H., Beijnen, J. H., Nooijen, W. J., Borst, P. & van Tellingen, O. (1996). Altered pharmacokinetics of vinblastine in mdr1a P-glycoprotein-deficient mice. J Natl Cancer Inst 88: 994–999.
Van Asperen, J., van Tellingen, O. & Beijnen, J. H. (1998). Determination of doxorubicin and metabolites in murine specimens by high-performance liquid chromatography. J Chromatogr B 712: 129–143.
Wacher, V. J., Wu, C-Y & Benet, L. Z. (1995). Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinogen 13: 129–134.
Webster, L. K., Cosson, E. J., Stokes, K. H. & Millward, M. J. (1996). Effect of the paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice. Br J Cancer 73: 522–524.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Asperen, J., Tellingen, O., Tijssen, F. et al. Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein. Br J Cancer 79, 108–113 (1999). https://doi.org/10.1038/sj.bjc.6690019
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690019
Keywords
This article is cited by
-
Identification of new candidate biomarkers to support doxorubicin treatments in canine cancer patients
BMC Veterinary Research (2021)
-
Targeting cancer via ribosome biogenesis: the cachexia perspective
Cellular and Molecular Life Sciences (2021)
-
Gender Differences in the Effect of Calcitriol on the Body Disposition and Excretion of Doxorubicin in Mice
European Journal of Drug Metabolism and Pharmacokinetics (2020)
-
Genetics of Anthracycline-Mediated Cardiotoxicity: Current Status and Challenges
Current Cardiovascular Risk Reports (2020)
-
Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration
Scientific Reports (2019)