title: Utilizing 19F NMR to investigate drug disposition early in drug discovery.
abstract: 1. Nuclear magnetic resonance (NMR), a non-selective and inherently quantitative method, has not been widely used as a quantitative tool for characterizing the disposition of lead molecules prior to clinical development. As a test case, we have chosen a fluoropyrimidine compound in lead optimization phase and evaluated its disposition following oral administration to rats using 19F NMR. 2. Urine, bile and feces from individual rats were profiled and the amount of dose eliminated in each matrix was calculated. The results indicated that, in male rats, the mean dose eliminated over 0-48 h was 40%, with 28% in urine, 9% in bile and 3% in feces. In female rats, the mean dose recovered in excreta over the same period was 55%, with 40% in urine, 8% in bile and 7% in feces. 3. In addition, plasma from rats and plasma from toxicology study in dogs were also profiled and exposure of circulating entities was determined. Plasma exposure determined by 19F NMR was in good agreement with those determined by conventional LC-MS/MS method, suggesting quantitative 19F NMR can be reliably used to estimate single dose or steady-state systemic exposure of circulating entities in animals and humans.
authors.affiliation: a Department of Discovery Chemistry and.
authors.forename: Haitao
authors.initials: H
authors.lastname: Hu
authors.affiliation: b Department of Drug Disposition , Lilly Research Laboratories , Indianapolis , IN , USA.
authors.forename: Naijia
authors.initials: N
authors.lastname: Huang
authors.affiliation: b Department of Drug Disposition , Lilly Research Laboratories , Indianapolis , IN , USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yi
authors.affiliation: b Department of Drug Disposition , Lilly Research Laboratories , Indianapolis , IN , USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Hui
authors.affiliation: a Department of Discovery Chemistry and.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Dally
authors.affiliation: b Department of Drug Disposition , Lilly Research Laboratories , Indianapolis , IN , USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Ehlhardt
authors.affiliation: b Department of Drug Disposition , Lilly Research Laboratories , Indianapolis , IN , USA.
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Kulanthaivel
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D005243:Feces / Q000737:chemistry; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D011743:Pyrimidines
keywords: Drug disposition; fluorine NMR; fluoropyrimidine; mass balance; metabolite profiling