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

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.