• Elzbieta Wyska.
• Department of Pharmacokinetics and Physical Pharmacy, Collegium Medicum, Jagiellonian University, Cracow, Poland. mfwyska@cyf-kr.edu.pl
• Pharmacology. 2010 Jan 1; 85 (5): 264-71.

AimsPentoxifylline and lisofylline are methylxanthine derivatives that exhibit anti-inflammatory activity both in vitro and in vivo. This study was designed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to describe the inhibitory effect of these compounds on TNF-alpha production in mice challenged with bacterial lipopolysaccharide (LPS).MethodsMale CD-1 mice received increasing intravenous doses of either compound simultaneously with high-dose LPS. A 2-compartment model with Michaelis-Menten-type elimination was used to describe the drug concentration versus time data. Serum TNF-alpha levels were fitted to an indirect response model.ResultsPentoxifylline and lisofylline reduced LPS-induced TNF-alpha serum concentrations in a dose-dependent manner. PK/PD analysis revealed an almost 2-fold higher estimate of K(m) for pentoxifylline in comparison to lisofylline. The production and elimination rates of TNF-alpha were: k(in) = 2,167 pg/ml * h(-1) and k(out) = 1.65 h(-1), respectively. The drug concentration causing 50% of TNF inhibition (IC(50)) was markedly lower for pentoxifylline (0.47 vs. 1.61 microg/ml).ConclusionsIt seems that pentoxifylline is more potent than lisofylline in inhibiting TNF-alpha production in vivo. The proposed PK/PD model allowed a better understanding of the pharmacological properties of both methylxanthine derivatives and may be helpful in appropriate dosage selection for further studies.Copyright 2010 S. Karger AG, Basel.

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