PMID: 11907177Mar 22, 2002Paper

Dose optimization of a doxorubicin prodrug (HMR 1826) in isolated perfused human lungs: low tumor pH promotes prodrug activation by beta-glucuronidase

The Journal of Pharmacology and Experimental Therapeutics
Thomas E MürdterBernhard Sperker

Abstract

HMR 1826 (N-[4-beta-Glucuronyl-3-nitrobenzyl-oxycarbonyl]doxorubicin) is a nontoxic glucuronide prodrug from which active doxorubicin is released by beta-glucuronidase. Preclinical studies aimed at dose optimization of HMR 1826, based on intratumoral pharmacokinetics, are important to design clinical studies. Using an isolated perfused human lung model, the uptake of doxorubicin into normal tissue and tumors after perfusion with 133 microg/ml (n = 6), 400 microg/ml (n = 10), and 1200 microg/ml (n = 6) HMR 1826 was compared. Extracellular tissue pH was measured, and enzyme kinetic studies were performed in vitro to investigate the effect of pH on the formation of doxorubicin. Extracellular pH was lower in tumors than in healthy tissue (6.46 +/- 0.35, n = 8 versus 7.30 +/- 0.33, n = 10; p < 0.001). In vitro, beta-glucuronidase activity was 10 times higher at pH 6.0 than at neutral pH. After perfusion with HMR 1826, there was a linear relationship between HMR 1826 concentrations in perfusate and normal lung tissue. After perfusion with 133, 400, and 1200 microg/ml HMR 1826, the final doxorubicin concentrations in normal and tumor tissue were 2.7 +/- 0.9, 11.1 +/- 5.4, and 21.8 +/- 8.4 microg/g (p < 0.05 for all comparisons), and 0...Continue Reading

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Citations

Nov 5, 2004·Naunyn-Schmiedeberg's Archives of Pharmacology·Christiane Kunert-KeilHeyo K Kroemer
Jan 14, 2012·Journal of the American Chemical Society·Ta-Chun ChengYu-Ling Leu
Jan 1, 2011·Innovations : Technology and Techniques in Cardiothoracic and Vascular Surgery·Reema Mallick, Todd Demmy
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Oct 24, 2012·Trends in Pharmacological Sciences·Georgia Sotiropoulou, Georgios Pampalakis
Feb 6, 2017·Langmuir : the ACS Journal of Surfaces and Colloids·Yuju ShihYung Chang
Mar 13, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·El Hassane AnouarAshik Mosaddik
May 29, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Garvey LiuJayanth Panyam
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Oct 26, 2005·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Angela R Eder, Edgar A Arriaga

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