Pharmacokinetic-pharmacodynamic modeling of methylxanthine derivatives in mice challenged with high-dose lipopolysaccharide.
OBJECTIVE
Pentoxifylline 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).


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-alpha levels were fitted to an indirect response model.


RESULTS
Pentoxifylline 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).


CONCLUSIONS
It 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.
Wyska
Elzbieta
E
Department of Pharmacokinetics and Physical Pharmacy, Collegium Medicum, Jagiellonian University, Cracow, Poland. mfwyska@cyf-kr.edu.pl
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008954:Models, Biological; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014970:Xanthines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; C025189:lisofylline; D010431:Pentoxifylline