Pharmacokinetics and pharmacodynamics of pentoxifylline and metabolites

Abstract: Pentoxifylline is a haemorheologic drug with complex pharmacokinetics and pharmacodynamics due to both reversible metabolism and the formation of active metabolites. In humans, pentoxifylline is metabolised to at least seven phase 1 metabolites (M1-M7). The reversible metabolism of pentoxifylline to the enantiomers of M1 has only been partly studied. This thesis investigates the pharmacokinetics of pentoxifylline and metabolites and their contributions to the haemorheological effects. When pentoxifylline is administered either orally or intravenously to healthy humans the plasma concentrations of M5 and S-M1 are higher than the pentoxifylline concentrations, whereas the ones for M4 are lower and R-M1 much lower. In-vitro studies showed that this can be mainly explained by a 15 times faster formation of S-M1 than R-M1 from pentoxifylline. Had the enantiomers been present at equal concentrations the reversible metabolism would have been 4 times faster from S-M1 than from R-M1. Pentoxifylline, R-M1, and M5 increases retinal blood flow after administration of pentoxifylline to healthy humans. In the following potency order R-M1, rac-M1, S-M1, pentoxifylline and M4 significantly inhibit platelet aggregation in a concentration-dependent manner in whole blood from healthy humans. The thesis also includes a phase two, double-blind, placebo-controlled randomised clinical trial investigating pentoxifylline and vitamin E treatment for prevention of radiation-induced side effects in 83 women with breast cancer. The study showed that the combination of pentoxifylline and vitamin E was well tolerated and may be used for prevention of some radiation-induced side effects, e.g. increased arm volume and pain described as stiffness in the skin.