Local disposition kinetics of floxuridine after intratumoral and subcutaneous injection as monitored by [F-19]-nuclear magnetic resonance spectroscopy in vivo

Purpose: To test the utility of [F-19]-nuclear magnetic resonance (NMR) spe ctroscopy for studying the kinetics of local drug disposition after interst itial application in vivo. Methods: Floxuridine at 30 mu mol (2.5% of the r eported i.p. 50% lethal dose, LD50) was injected into rats either intratumo rally (Morris hepatoma M3924A) or s.c. [F-19]-NMR spectra were obtained at the site of administration for up to 5 h after injection using a 2-cm diame ter surface coil at 2.0 T. Signal-time data obtained for floxuridine and th e metabolite 5-fluorouracil were analyzed using linear compartment models. Results: The lower limit for the quantitation of drug remaining at the site of administration was 1 mu mol for tumors and 0.2 mu mol for the s.c. inje ction site. Local drug disposition was biexponential in four of six tumors where the half-lives of the fast and slow components of disposition ranged from 4 to 26 and from 33 to 289 min, respectively. It was monoexponential i n the remaining two tumors (half-lives 49 and 128 min) and in the s.c. inje ction experiments (n = 4, half-life 6-9 min). 5-Fluorouracil could be quant itated in three of six tumors; the estimated fraction of floxuridine conver ted intratumorally into 5-fluorouracil was 11-23%. alpha-Fluoro-beta-alanin e was detected in the sum spectra of three of the six tumours. Conclusions: Local drug-disposition kinetics after interstitial application can be moni tored noninvasively by in vivo [F-19]-NMR spectroscopy. Disposition kinetic s after local injection is highly variable and has a slow component in this tumor, whereas it is much less variable and relatively fast in subcutaneou s tissue. The results suggest that NMR spectroscopy may be useful for in vi vo studies of drug release from depot preparations designed for interstitia l application.