Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans.
It is known that pentoxifylline inhibits platelet aggregation in vitro, but the effects from pentoxifylline and its main metabolites: 3,7-dimetyl-1(5 hydroxyhexyl)xanthine (R-M1 and S-M1), 3,7-dimetyl -1(4-carboxybutyl)xanthine (M4), 3,7-dimetyl -1(3-carboxypropyl)xanthine (M5), on platelet aggregation in whole blood in vitro and in vivo have not been studied. We found that pentoxifylline, rac-M1, R-M1, S-M1 and M4 significantly inhibit ADP induced platelet aggregation in whole blood in vitro in a concentration-dependent manner, R-M1 being the most potent followed by rac-M1, S-M1, pentoxifylline, and M4. In this series of experiments the effects on aggregation induced ATP-release were less pronounced and were only significant after treatment with pentoxifylline, rac-M1 and R-M1, but the potency order appears to be the same. Since the metabolites are not available for use in humans, and also since each substance would be extensively metabolised in vivo, we made an attempt to estimate the relative contribution of each substance to the total effect of pentoxifylline in vivo. Previously published concentrations of pentoxifylline and these metabolites in humans, after administration of pentoxifylline, were used in combination with the potency ratios from this study. The findings from these calculations were that the main effect in vivo comes from S-M1 followed by pentoxifylline, the other metabolites contribute less than 10% each.


CONCLUSIONS
in the following potency order R-M1, rac-M1, pentoxifylline, S-M1 and M4 all have significant effects on platelet aggregation in whole blood in vitro. However, it appears that the main effects in vivo are caused by S-M1 and pentoxifylline.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010431:Pentoxifylline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism
D010975:Platelet Aggregation Inhibitors; C047155:1-(4'-carboxybutyl)-3,7-dimethylxanthine; D000244:Adenosine Diphosphate; C047154:1-(3'-carboxypropyl)-3,7-dimethylxanthine; D000255:Adenosine Triphosphate; C025189:lisofylline; D010431:Pentoxifylline