Influence of inflammatory disorders on pharmacokinetics of lisofylline in rats: implications for studies in humans

Abstract

1. Despite the number of favourable properties of lisofylline (LSF), clinical trials on this compound have not yielded the expected results yet.

2. The aims of this study were to evaluate the pharmacokinetics of LSF enantiomers in rats following intravenous, oral and subcutaneous administration of (±)-LSF and to assess the influence of experimental inflammatory disorders, such as multiple organ dysfunction syndrome and severe sepsis on LSF pharmacokinetics.

3. In addition, based on the results obtained an attempt was made to elucidate the possible reasons for the failure of LSF therapy in clinical trials carried out in patients with severe inflammatory disorders.

4. A subcutaneous route of (±)-LSF administration to rats is more favourable than an oral one due to a high bioavailability and a fast absorption of both LSF enantiomers. Pharmacokinetics of LSF in rats is significantly influenced by inflammatory diseases. Too low LSF serum levels might have been one of the reasons for clinical trial failures. A long-term i.v. infusion of LSF seems to be more effective compared to short-term multiple infusions that were used in clinical trials, as it may provide concentrations above IC₅₀ for inhibition of both TNF-alpha release and cAMP degradation in serum for a longer period of time.

Keywords:

• Lisofylline
• phosphodiesterase inhibitors
• pharmacokinetics
• sepsis
• multiple organ dysfunction syndrome
• inflammation

Disclosure statement

No potential conflict of interest was reported by the authors.

Compliance with ethical standards

All the experimental procedures and protocols involving animals were approved by the First Local Ethical Committee on Animal Testing at the Jagiellonian University in Cracow and were conducted in accordance with the European Communities Council Directive of 22 September 2010 (2010/63/EU).

Additional information

Funding

This work was supported by Statutory Funds of the Jagiellonian University Medical College, Cracow, Poland under Grants numbers K/ZDS/007070 and K/DSC/003548.