Macromolecular interactions of [14C-ring]melphalan in blood.

The pharmacokinetics and macromolecular interactions of [14C-ring]melphalan (L-PAM) in blood were studied in rats following a single oral dose (20 mg/kg, 0.1 mCi/kg). Radioactivity levels were monitored in blood over a period of 72 hr. The highest levels of radioactivity were observed at 2 hr. The decline of radioactivity from the blood was biphasic with T1/2 alpha = 7 hr and T1/2 beta = 75 hr. The radioactive species in plasma corresponded to unchanged L-PAM and its two known hydrolytic products 4,2-hydroxyethyl 2-chloroethylamino-L-phenylalanine (L-MOH) and 4-[bis(2-hydroxyethyl)amino]-L-phenylalanine (L-DOH). In addition, four other major, previously unknown, metabolites of L-PAM were detected in plasma. At 72 hr, most of the radioactivity was bound to macromolecular components, 26% to plasma macromolecules and 62% in red blood cells. Covalent binding to blood cells was mainly to membrane proteins. Binding to hemoglobin and other soluble components of the red cells was also observed, with a 5000-fold greater affinity for membranes. These studies suggest extensive interaction of melphalan, or its metabolites, with membrane and soluble proteins of red blood cells.