WHOLE-BODY DISPOSITION AND POLYGLUTAMATE DISTRIBUTION OF THE GAR FORMYLTRANSFERASE INHIBITORS LY309887 AND LOMETREXOL IN MICE - EFFECT OF LOW-FOLATE DIET
Ll. Habeck et al., WHOLE-BODY DISPOSITION AND POLYGLUTAMATE DISTRIBUTION OF THE GAR FORMYLTRANSFERASE INHIBITORS LY309887 AND LOMETREXOL IN MICE - EFFECT OF LOW-FOLATE DIET, Cancer chemotherapy and pharmacology, 41(3), 1998, pp. 201-209
Purpose: The whole-body autoradiographic distribution of two radiolabe
led antifolate inhibitors of GAR formyltransferase, lometrexol and LY3
09887, were compared in tumor-bearing mice maintained on standard diet
(SD) and a low-folate diet (LFD) in order to determine the total amou
nts of drug that accumulated in blood, tumor, liver and kidney. The ti
me-dependent changes in tissue distribution were evaluated over a 7-da
y period in order to compare the pharmacokinetic properties of both in
hibitors and to assess the influence of dietary folate on this distrib
ution. In addition, the effect of dietary folate on polyglutamation of
compound accumulating in the liver was measured. The results have bea
ring on the potential of these two clinical agents to produce delayed
toxicity in cancer patients and the use of dietary folate to modulate
or prevent the development of this toxicity. Methods: Single equimolar
i.v. doses of [C-14]LY309887 and [C-14]lometrexol were administered t
o C3H mammary tumor bearing mice on SD or LFD. and the disposition of
these compounds was quantitated using whole-body autoradiography. Live
rs were also harvested and extracted for determination of polyglutamat
e distribution. Animals were sacrificed both early and late (7 days) a
fter dosing to determine the long-term retention of these compounds. R
esults: Whole-body autoradiography revealed that the highest concentra
tions of both compounds were in liver and kidney. Concentrations of bo
th compounds were two-fold higher in livers from LFD mice than in live
rs from SD mice. Lometrexol concentrations in liver averaged 2.8- and
2.2-fold higher than LY309887 in SD and LFD livers, respectively. In S
D livers, the polyglutamate profiles of both compounds were similar, w
ith hexaglutamates being the longest chain species detected. In LFD li
vers, hexaglutamates of LY309887 were observed, while hepta-and octagl
utamates of lometrexol were detected after 168 h. Conclusions: The red
uced hepatic retention and biochemical profile of LY309887 compared to
lometrexol suggest that it may be less likely to produce delayed cumu
lative toxicity while still retaining antitumor activity. However, the
increased hepatic accumulation observed in LFD mice emphasizes the im
portance of assessing and supplementing folate in cancer patients trea
ted with this class of compounds.