Whole-body disposition and polyglutamate distribution of the GAR formyltransferase inhibitors LY309887 and lometrexol in mice: effect of low-folate diet.
OBJECTIVE
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.


METHODS
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 dosing to determine the long-term retention of these compounds.


RESULTS
Whole-body autoradiography revealed that the highest concentrations of both compounds were in liver and kidney. Concentrations of both compounds were two-fold higher in livers from LFD mice than in livers from SD mice. Lometrexol concentrations in liver averaged 2.8- and 2.2-fold higher than LY309887 in SD and LFD livers, respectively. In SD livers, the polyglutamate profiles of both compounds were similar, with hexaglutamates being the longest chain species detected. In LFD livers, hexaglutamates of LY309887 were observed, while hepta- and octaglutamates of lometrexol were detected after 168 h.


CONCLUSIONS
The reduced hepatic retention and biochemical profile of LY309887 compared to lometrexol suggest that it may be less likely to produce delayed cumulative toxicity while still retaining antitumor activity. However, the increased hepatic accumulation observed in LFD mice emphasizes the importance of assessing and supplementing folate in cancer patients treated with this class of compounds.
Habeck
L L
LL
Department of Cancer Research, Lilly Research Laboratories, Indianapolis, Indiana 46285, USA.
Chay
S H
SH
Pohland
R C
RC
Worzalla
J F
JF
Shih
C
C
Mendelsohn
L G
LG
D000818:Animals; D001345:Autoradiography; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D051026:Phosphoribosylglycinamide Formyltransferase; D013763:Tetrahydrofolates / Q000493:pharmacokinetics*; D014018:Tissue Distribution
C105065:6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C045894:lometrexol; D005492:Folic Acid; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase