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
L L HabeckL G Mendelsohn

Abstract

The whole-body autoradiographic distribution of two radiolabeled antifolate inhibitors of GAR formyltransferase, lometrexol and LY309887, were compared in tumor-bearing mice maintained on standard diet (SD) and a low-folate diet (LFD) in order to determine the total amounts of drug that accumulated in blood, tumor, liver and kidney. The time-dependent changes in tissue distribution were evaluated over a 7-day period in order to compare the pharmacokinetic properties of both inhibitors and to assess the influence of dietary folate on this distribution. In addition, the effect of dietary folate on polyglutamation of compound accumulating in the liver was measured. The results have bearing 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. Single equimolar i.v. doses of [14C]LY309887 and [14C]lometrexol were administered to C3H mammary tumor bearing mice on SD or LFD, and the disposition of these compounds was quantitated using whole-body autoradiography. Livers were also harvested and extracted for determination of polyglutamate distribution. Animals were sacrificed both early and late (7 days) after do...Continue Reading

Citations

Oct 7, 2005·Nutrition in Clinical Practice : Official Publication of the American Society for Parenteral and Enteral Nutrition·Kim Robien
Jun 28, 2001·Oncogene·J Adams, P J Elliott
Mar 26, 2004·Biochemical Pharmacology·Jan Hendrik HooijbergGodefridus J Peters

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