Abstract
The metabolism and disposition of LY231514 was studied in mice and dogs. 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 compound showed high plasma levels, resulting in AUC values of 30–33 μg-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 were 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 major excretion pathway in mice after single iv doses of [14C]LY231514. Urine constituted the major route of excretion in dogs. Parent LY231514 accounted for the majority of urinary radiocarbon in mice (90%) and dogs (68%). Minor metabolites were found in urine, but the amounts were too small to isolate or identify. Based on an earlier observation that LY231514 photodegraded to produce reaction products having similar retention times as these minor urinary isolates, a photo-oxidation system was developed which in fact produced these metabolites. Subsequently, these photolytically-produced materials were used as standards to identify two novel in vivo metabolites formed by oxidation of the pyrrolo-pyrimidine ring system of LY231514. The oxidative transformations are similar to those observed for tryptophan and other indoles in that the pyrrole ring is oxidized to give an amide; further oxidation cleaves this ring, one ring carbon is lost, and a ketone is formed.
Footnotes
-
Send reprint requests to: William J. Ehlhardt, 0825 Department of Drug Metabolism, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. E-mail:Ehlhardt_W{at}lilly.com
- Abbreviations used are::
- LY231514 Na2
- N-[4-[[2-(Amino–4,7-dihyro-4oxo-3H-pyrrolo-[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid disodium
- LY282038
- N-[4-[[2-(Methyl–4,7-dihyro-4-oxo-3H-pyrrolo-[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl-L-glutamic acid disodium
- TS
- thymidylate synthetase
- DHFR
- dihydrofolate reductase
- GARFT
- glycinamide ribonucleotide formyltransferase
- TFA
- trifluoroacetic acid
- Cal’d.
- calculated
- HMQC
- Heteronuclear Multiple-Quantum Correlation
- HMBC
- Heteronuclear Multiple Bond Correlation
- ROESY
- rotating frame Overhauser enhancement spectroscopy
- HRMS
- High Resolution Mass Spectrometry
- DMSO
- dimethyl sulfoxide
- DMF
- dimethyl formamide
- RT
- room temperature
- Received October 21, 1996.
- Accepted February 12, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|