Serum Concentrations of Pentoxifylline and its Metabolites in Premature Infants with Sepsis when Administered by Continuous Intravenous Infusion

Abstract

Pentoxifylline, a methylxanthine derivative, and some of its metabolites have demonstrated an immunomodulatory effect both in-vivo and in-vitro. Therefore, pentoxifylline may play a potential role in the treatment of septic shock. The aim of this study was to evaluate serum concentrations of pentoxifylline and its clinically important metabolites (M1, M4 and M5) in a population of septic preterm neonates treated with pentoxifylline. The study was carried out on a group of 12 premature infants. Pentoxifylline was given once daily in a normalized dose of 5 mg kg−1 h−1, as a 6- or 12-h intravenous continuous infusion on three consecutive days. Serum concentrations were assayed by HPLC with solid-phase extraction. The results showed that a two-fold increase in the pentoxifylline dose (from 30 to 60 mg kg−1 day−1) resulted in a statistically significant increase in not only pentoxifylline, but also M1 metabolite serum concentrations compared with serum concentrations of M4 and M5 metabolites. Our data indicated that despite the high serum levels of the analysed compounds (with the M1 metabolite attaining the highest level), large doses of pentoxifylline were well tolerated. From the pharmacokinetic point of view, a longer, 12 h, infusion of pentoxifylline achieves serum concentrations of the drug which may be effective in inhibiting the production of some inflammatory mediators. Therefore, administration of pentoxifylline seems to be of benefit in the treatment of sepsis. However, further investigation of the efficacy and safety of this drug and its active metabolites in severe infections is warranted.