A Systems Pharmacology Model of Anandamide Dynamics After FAAH Inhibitor Administration
Metelkin E.(1), Bagrova N.(1), Demin O.(1), Benson N.(2)
(1) Institute for Systems Biology SPb, Leninskie Gory 1/75G, Moscow; (2) Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.
Objectives: Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme hydrolyzing the anandamide and related amidated lipids. Previously it was shown preclinically that the inactivation of FAAH produces analgesic, anti-inflammatory, anxiolytic, and antidepressant effects indicating that FAAH may be a promising therapeutic target. This work describes a detailed mathematical model of anandamide and other ethanolamides kinetics that have been used for analysis of clinical data of PF-04457845 (Pfizer), a highly selective inhibitor of FAAH.
Methods: The developed model includes the synthesis and hydrolysis of five major ethanolamides (AEA, OEA, PEA, LEA, SEA) in different tissues and organs as well as the processes of ethanolamides distribution. The detailed kinetic mechanism of each process was included into the model. The partial and global models wee verified on the basis of published data on enzyme kinetics and clinical trial data of Pfizer.
Results: The developed model is able to simulate anandamide dynamics in man over a wide range of different conditions, including inhibition of different steps of whole pathway, different inhibitors and doses. It also can predict the optimal administration regime as well as combinations of different drugs.
Conclusions: The current analysis was consistent with the presence of a second enzyme that hydrolyses ethanolamides that is not inhibited by PF-04457845, but can limit the maximal levels of ethanolamides at high inhibition of FAAH. We suggest a possible candidate is NAAA enzyme that is able to hydrolyse ethanolamides with high activity. The implications of this for end points such as occupancy at the cannabinoid receptor will be discussed.
