Utilizing 19F NMR to investigate drug disposition early in drug discovery

• Published in: Xenobiotica Vol. 45; no. 12; pp. 1081 - 1091
• Main Authors: Hu, Haitao, Huang, Naijia, Yi, Ping, Hui, Yu-Hua, Dally, Robert D., Ehlhardt, William J., Kulanthaivel, Palaniappan
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 2015
• Subjects: Animals; Bile - chemistry; Biotransformation; Dogs; Drug Discovery - methods; Drug disposition; Feces - chemistry; Female; fluorine NMR; Fluorine Radioisotopes - pharmacokinetics; fluoropyrimidine; Humans; Isotope Labeling; Magnetic Resonance Spectroscopy - methods; Male; mass balance; metabolite profiling; Pyrimidines - pharmacokinetics; Pyrimidines - toxicity; Rats; Rats, Sprague-Dawley; Tissue Distribution; fluorine NMR; fluoropyrimidine; Drug disposition; mass balance; metabolite profiling
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2015.1040866

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 19 F 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 19 F NMR was in good agreement with those determined by conventional LC-MS/MS method, suggesting quantitative 19 F NMR can be reliably used to estimate single dose or steady-state systemic exposure of circulating entities in animals and humans.