Pharmacokinetics and pharmacodynamics of pentoxifylline and metabolites

Pentoxifylline increases erythrocyte flexibility, reduces blood viscosity,and inhibits platelet aggregation and is thus used in the treatment of peripheral vasculardisease. It is transformed into at least seven phase I metabolites, of which two, M1 andM5, are active. The reduction of the keto group of pentoxifylline to a secondary alcoholin M1 takes place chiefly in erythrocytes, is rapidly reversible, and creates a chiralcenter. The aims of this study were: to develop HPLC methods to separate the enantio-mers of M1, to investigate the kinetics of the reversible biotransformation of pentoxi-fylline to (R)and (S)-M1 in hemolysed erythrocyte suspension, and to quantify theformation of the enantiomers of M1 (as well as M4 and M5) after intravenous and oraladministration of pentoxifylline to human volunteers. (R)and (S)-M1 could be separatedpreparatively on a cellobiohydrolase column, while determination in blood or plasma wasby HPLC after chiral derivatization with diacetyl-L-tartaric acid anhydride. The metabo-lism of pentoxifylline to (R)-M1 in suspensions of hemolysed erythrocytes followedsimple Michaelis-Menten kinetics (Km = 11 mM), while that to (S)-M1 was best de-scribed by a two-enzyme model (Km = 1.1 and 132 mM). Studies with inhibitors indicatedthat the enzymes were of the carbonyl reductase type. At a therapeutic blood concen-tration of pentoxifylline, the calculated rate of formation of (S)-M1 is 15 times higherthan that of the (R)-enantiomer. Back-conversion of M1 to pentoxifylline was 3–4 timesfaster for the (S)than for the (R)-enantiomer. In vivo, the R:S plasma concentration ratioof M1 ranged from 0.010–0.025 after intravenous infusion of 300 or 600 mg of pentoxi-fylline, and from 0.019–0.037 after oral administration of 600 mg. The biotransformationof pentoxifylline to M1 was thus highly stereoselective in favor of the (S)-enantiomerboth in vitro and in vivo. Chirality 14:643–652, 2002. © 2002 Wiley-Liss, Inc.