Tissue distribution and macromolecular interactions of 14[C-ring] melphalan in the rat

The kinetics of uptake and elimination, covalent binding, and macromolecular interactions of 14[C-ring] melphalan was studied after a single oral dose (20 mg/kg, 0.1 mCi/kg) in normal rats. Peak radioactivity level in tissues was observed at 2-4 h after administration. Uptake of label in most tissues was rapid, with a t1/2 of less than 1 h. Elimination was biphasic. Tissues of the gastrointestinal tract showed the most rapid rates of elimination, with t1/2 beta of 13, 24, 18, and 19 h for stomach, duodenum, and small and large intestines, respectively. Bone marrow also showed a fast rate of elimination of radioactivity, with a t1/2 beta of 30 h. Tissues with the slowest rates of elimination were skin, eye, spleen, pancreas, and lung, with t1/2 beta of 333, 241, 149, 122, and 109 h, respectively. Covalent binding studies showed that melphalan, or its metabolites, bound irreversibly to all tissue macromolecular fractions. The percentage of covalently bound radioactivity increased with time in all tissues except kidney and eye, reaching up to 70%-80% of the total radioactivity remaining at 72 h. Elimination of covalently bound radioactivity was slower in the DNA fractions of the tissues of the gastrointestinal tract and heart compared with the elimination rate from lipid, protein, or RNA fractions. Slow elimination rates of 14[C-ring] melphalan equivalents from the protein fraction were observed in the skin, eye, and brain. Accumulation, rather than elimination, of radioactivity in this fraction was most prominent in the pancreas. In the bone marrow accumulation of radioactivity was observed in the lipid fraction.