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Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours.

Abstract：

:Bilateral kidney ligation of mice immediately before injection of misonidazole (MIS) prolongs the plasma half-life of this radiosensitizer from about 2 h (in normal mice) to 10-11 h, similar to that in man. Kidney ligation does not, however, change the relative proportions of MIS and its O-demethylated metabolite, Ro-05-9963, for the first 12 h after MIS injection. Kidney ligation was used with the two radiosensitizers, MIS and Ro-05-9963, to investigate the influence of plasma half-life both on peak plasma levels and on the tumour/plasma ratio of sensitizer concentration in the EMT6 mouse tumour. Although the acute LD50 of Ro-05-9963 in normal mice was twice that of MIS, this apparent advantage was offset by peak tumour levels 50% or less of those achieved by equimolar injected doses of MIS. However, by comparing the plasma and tumour levels in mice in which the drug half-lives were prolonged by bilateral kidney ligation, it was concluded that the lower plasma and tumour levels of Ro-05-9963 were a result of its shorter plasma half-life, rather than of an intrinsic barrier to tumour penetration. Because of this rapid clearance, the radiosensitization produced by Ro-05-9963 was less than that produced by equimolar injected doses of MIS. As this difference did not occur in kidney-ligated mice, and hence would not be expected to occur in man, the comparison of MIS and Ro-05-9963 in mice produces an artificially low radiosensitization for Ro-05-9963 and possibly also for other compounds with short plasma half-lives. Although the short plasma half-life of Ro-05-9963 appeared to be responsible for its low peak plasma concentration, it did not produce a low tumour/plasma ratio. Within the limits of plasma nitroimidazole half-lives investigated (0.5-10 h) the tumour/plasma ratio was insensitive to plasma half-life, being 50-70% for both MIS and Ro-05-9963 in both normal and kidney-ligated mice. It is concluded that the common assumption that tumour/plasma ratios of MIS in the mouse are less than those in man is unjustified.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Brown JM,Yu NY,Workman P

doi

10.1038/bjc.1979.55

subject

Has Abstract

pub_date

1979-03-01 00:00:00

pages

310-20

issue

eissn

0007-0920

issn

1532-1827

journal_volume

pub_type

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Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours.