Influence of inflammatory disorders on pharmacokinetics of lisofylline in rats: implications for studies in humans. (3rd October 2019)

• Record Type: Journal Article
• Authors: Świerczek, Artur; Wyska, Elżbieta; Pociecha, Krzysztof; Baś, Sebastian; Mlynarski, Jacek
• Is Part Of: Xenobiotica. Volume 49:Number 10(2019:Oct.)
• Page Start: 1209
• Page End: 1220
• Publication Date: 2019-10-03
• Subjects: Lisofylline -- phosphodiesterase inhibitors -- pharmacokinetics -- sepsis -- multiple organ dysfunction syndrome -- inflammation; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2018.1542516
• Languages: English
• ISSNs: 0049-8254

Abstract

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.