PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response.

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Swierczek A, Wyska E, Bas S, Woyciechowska M, Mlynarski J

PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response.

Naunyn Schmiedebergs Arch Pharmacol. 2017 Oct;390(10):1047-1059. doi: 10.1007/s00210-017-1406-z. Epub 2017 Jul 20.

PubMed ID

28730281 [ View in PubMed

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Abstract

In recent years, phosphodiesterase (PDE) inhibitors have been frequently tested for the treatment of experimental inflammatory and immune disorders. It is suggested that anti-inflammatory properties of PDE inhibitors are related to their ability to increase cAMP levels. The aim of this study was to verify the hypothesis that cAMP may be a useful marker of pharmacological response following administration of non-selective PDE inhibitors (pentoxifylline and (+/-)-lisofylline) to endotoxemic rats. Male Wistar rats were administered LPS (1 mg kg(-1), i.v.) simultaneously with either compound given at two doses (40 and 80 mg kg(-1), i.v.). Levels of cAMP and both compounds in animal plasma were measured by the validated HPLC methods. Pharmacokinetic-pharmacodynamic analysis was performed using basic and modified indirect response (IDR) models II in Phoenix WinNonlin. The results of this study indicate that, in contrast to pentoxifylline, (+/-)-lisofylline demonstrates a non-linear pharmacokinetics in rats with endotoxemia. In vitro study using human recombinant PDE4B and PDE7A revealed the occurrence of additive interaction between studied compounds. Moreover, (+/-)-lisofylline is a more potent inhibitor of PDEs compared to pentoxifylline, as evidenced by lower IC50 values. Following administration of both compounds, levels of cAMP in rat plasma increased in a dose-dependent manner. The modified IDR model II better described cAMP levels over time profiles. The validity of the proposed marker was confirmed by measuring plasma TNF-alpha levels in the studied animals. In conclusion, cAMP may be used in future preclinical and clinical studies of some PDE inhibitors to evaluate the drug concentration-effect relationship.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pentoxifylline	Phosphodiesterase enzymes	Group	Humans	Yes	Inhibitor	Details