METABOLISM OF LISOFYLLINE AND PENTOXIFYLLINE IN HUMAN LIVER-MICROSOMES AND CYTOSOL

The metabolism of lisofylline and pentoxifylline were examined in cyto sol and microsomes prepared from four human livers to determine whethe r pentoxifylline is likely to serve as an efficient prodrug for the mo re active inhibitor of phosphatidic acid-dependent cell signaling, lis ofylline, and to determine the extent to which lisofylline is converte d to pentoxifylline, a hemorheologic agent used for the treatment of i ntermittent claudication. Pentoxifylline is exclusively reduced to the optical antipode of lisofylline (S M-1) in human liver cytosol, where as the reduction in microsomes is 85% stereoselective in favor of S M- 1 formation. The intrinsic clearance (V-max/K-M) of S M-1 formation in cytosol was 4 times that in microsomes. In human liver microsomes. S M-1 is exclusively converted to pentoxifylline, whereas similar to 45% of lisofylline oxidation is accounted for by the formation of pentoxi fylline and the balance by aliphatic diols. It is concluded that pento xifylline is an inefficient predrug for delivery of lisofylline and th at formation of pentoxifylline accounts for similar to 40% of the micr osomal metabolites formed from lisofylline at substrate concentrations likely to be encountered in human therapeutic applications.