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 0.7 +/- 0.3, 8.6 +/- 2.0 microg/g (p < 0.01 versus 133 microg/g), and 8.7 +/- 4.9 microg/g, respectively. This agrees with the
enzyme kinetic observations of saturation of
beta-glucuronidase at 400 microg/ml
HMR 1826 in the acidic environment of the
tumor. Therefore, the escalation of the
HMR 1826 dose most likely results in higher circulating concentrations than 400 microg/ml but does not increase the uptake of
doxorubicin into
tumors and, subsequently, antitumor efficacy. The isolated perfused human lung is an excellent model for preclinical investigations aimed at optimization of tissue pharmacokinetics of
tumor-selective
prodrugs.