METABOLISM AND DISPOSITION OF THE ANTIFOLATE LY231514 IN MICE AND DOGS

The metabolism and disposition of LY231514 was studied in mice and dog s, LY231514 is a novel pyrrolopyrimidine-based multi-target antifolate (MTA) showing broad in vivo antitumor activity in mouse models and is currently in phase II human clinical trials. Doses (iv) of the compou nd showed high plasma levels, resulting in AUC values of 30-33 mu g-hr /ml for mice and dogs after 20 and 7.5 mg/kg doses, respectively, The compound was eliminated rapidly, Half-life values for mice and dogs we re about 7 and 2 hr, respectively, In vitro plasma binding measured 56 % in mice, 46% in dogs, and 81% in humans. Fecal elimination was the m ajor excretion pathway in mice after single iv doses of [C-14]LY231514 , Urine constituted the major route of excretion in dogs. Parent LY231 514 accounted for the majority of urinary radiocarbon in mice (90%) an d dogs (68%), Minor metabolites were found in urine, but the amounts w ere too small to isolate or identify, Based on an earlier observation that LY231514 photodegraded to produce reaction products having simila r retention times as these minor urinary isolates, a photo-oxidation s ystem was developed which in fact produced these metabolites, Subseque ntly, these photolytically-produced materials were used as standards t o identify two novel in vivo metabolites formed by oxidation of the py rrolo-pyrimidine ring system of LY231514, The oxidative transformation s are similar to those observed for tryptophan and other indoles in th at the pyrrole ring is oxidized to give an amide; further oxidation cl eaves this ring, one ring carbon is lost, and a ketone is formed.