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.
D000818:Animals; D004912:Erythrocytes / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006868:Hydrolysis; D046911:Macromolecular Substances; D008297:Male; D008558:Melphalan / Q000097:blood*; D008565:Membrane Proteins / Q000097:blood; D010949:Plasma / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D006454:Hemoglobins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D008558:Melphalan