Pharmacokinetic-Pharmacodynamic Modeling of Methylxanthine Derivatives in Mice Challenged with High-Dose Lipopolysaccharide

Abstract

Aims: Pentoxifylline and lisofylline are methylxanthine derivatives that exhibit anti-inflammatory activity both in vitroand in vivo. This study was designed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to describe the inhibitory effect of these compounds on TNF-α production in mice challenged with bacterial lipopolysaccharide (LPS). Methods: Male 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-α levels were fitted to an indirect response model. Results: Pentoxifylline and lisofylline reduced LPS-induced TNF-α 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-α 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 (IC₅₀) was markedly lower for pentoxifylline (0.47 vs. 1.61 µg/ml). Conclusions:It seems that pentoxifylline is more potent than lisofylline in inhibiting TNF-α 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.

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

“…The applied model is a modified indirect response model (19) with implemented transit compartments (T 1 -T 4 ) that describe the delay of the observed pharmacodynamic response. In this scheme τ is the mean transit time, k in is the time limited (from 0 to t lag ) zero-order rate constant of production of a TNF-α precursor (e.g., TNF-α mRNA).…”

Cancer treatment-induced oral mucositis: a critical review

“…Pentoxifylline is a synthetic derivative of dimethylxanthine, which is chemically paired with theophylline and caffeine, but in contrast to these drugs, pentoxifylline has haematological effects that are useful in the symptomatic treatment of complications of peripheral vascular diseases 154 . Pentoxifylline is a medicine that acts in different ways: it relaxes the blood vessel wall to make it easier for blood to pass through them; it increases the amount of blood that reaches the tissues; it stops platelet aggregation as it increases the formation of prostacyclin; and it reduces the viscosity of blood.…”

Pharmacokinetic/Pharmacodynamic Modeling in Inflammation

“…33 The immune mediators are usually measured by two methods. The first is use of immunoassays, such as enzymelinked immunosorbent assays (ELISAs) 28–31,33–35 and radioimmunoassay (RIA), 36 and the other is ex vivo measurement of enzyme activity. 24,25,37 When measurement of protein concentrations of the mediators is not feasible (usually due to assay insensitivity), mRNA concentrations may be obtained by polymerase chain reaction (PCR) and used as a surrogate.…”

“…19,28,30,31,35,36 Gozzi et al published a PK/PD model to describe the lag time observed for increase in TNFα after LPS induction and effect of susalimod. 30 This model is essentially a precursor IDR.…”

“…30 This model is essentially a precursor IDR. 76 It was modified by Chakraborty et al 28 and Wyska 31 for fitting time courses of TNFα and other mediators after LPS induction along with drug inhibition.…”