RT Journal Article
SR Electronic
T1 Metabolism of lisofylline and pentoxifylline in human liver microsomes and cytosol.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1174
OP 1179
VO 24
IS 11
A1 Lillibridge, J A
A1 Kalhorn, T F
A1 Slattery, J T
YR 1996
UL http://dmd.aspetjournals.org/content/24/11/1174.abstract
AB The metabolism of lisofylline and pentoxifylline were examined in cytosol and microsomes prepared from four human livers to determine whether pentoxifylline is likely to serve as an efficient prodrug for the more active inhibitor of phosphatidic acid-dependent cell signaling, lisofylline, and to determine the extent to which lisofylline is converted to pentoxifylline, a hemorheologic agent used for the treatment of intermittent claudication. Pentoxifylline is exclusively reduced to the optical antipode of lisofylline (S M-1) in human liver cytosol, whereas the reduction in microsomes is 85% stereoselective in favor of S M-1 formation. The intrinsic clearance (Vmax/KM) 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 approximately 45% of lisofylline oxidation is accounted for by the formation of pentoxifylline and the balance by aliphatic diols. It is concluded that pentoxifylline is an inefficient prodrug for delivery of lisofylline and that formation of pentoxifylline accounts for approximately 40% of the microsomal metabolites formed from lisofylline at substrate concentrations likely to be encountered in human therapeutic applications.