Estramustine (EaM), a
carbamate ester of 17beta-estradiol and
nor-nitrogen mustard, is a cytotoxic compound with antitumoral effect in
malignant glioma in vitro and in vivo . However, knowledge of the pharmacokinetics of EaM in experimental
glioma is limited. The objective of this study was therefore to investigate further the distribution of EaM in the BT4C rat
glioma model. Assessment of EaM uptake and distribution was performed by quantitative whole-body autoradiography. In addition, the uptake of EaM and its metabolites
estromustine (EoM),
estradiol, and
estrone were analyzed by gas chromatography. EaM was taken up from the circulation and was found to be the main product in
glioma tissue. Whole-body autoradiography after [14C]-EaM administration revealed a strong 14C label simultaneously in
tumor and normal brain tissue at 0.5 h after
drug administration. In
tumor tissue, sustained high levels of 14C label were detected at 12 h after
drug administration. In contrast to the
tumor, radioactivity in normal brain tissue rapidly leveled off, indicating a retention of radioactivity in the
tumor. The
tumor/brain radioactivity ratio reached a peak of 4.5 at 12 h after
drug administration. High levels of 14C label were also found in pulmonary tissue. By gas chromatography, EoM was found to be the main metabolite in plasma. However, EaM reached higher levels in
tumor tissue, with the mean
tumor/plasma ratio being 11.7 as compared with 2.0 for EoM. Only low plasma levels of the
estrogen metabolites were detected. In conclusion, EaM is taken up in the BT4C rat
glioma tissue and is retained in the
tumor as compared with normal brain tissue and plasma. EaM showed a greater selectivity for
tumor tissue, exhibiting a high
tumor/plasma ratio as compared with EoM. The distribution pattern after administration of EaM, as evaluated by both whole-body autoradiography and gas chromatography, supports the earlier suggestion that the uptake is related to a
protein with EaM-binding characteristics.