DISTRIBUTION, METABOLISM AND ELIMINATION OF BIA 10‐2474 IN THE RAT

Abstract

In January 2016 one person died and others suffered adverse neurological effects during a Phase I clinical trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10‐2474. We have evaluated the distribution, metabolism and excretion of BIA 10‐2474 in the rat.BIA 10‐2474 distribution and excretion was evaluated in Wistar rats after oral administration (30 mg/kg) of [14C]‐BIA 10‐2474. The metabolic profiling of BIA 10‐2474 was evaluated, in the same species, after oral administration of 90 mg/kg [14C]‐BIA 10‐2474.The mean observed Cmax of total radioactivity in plasma occurred at 1 h and it was detectable up to 72h post‐dosing with 30 mg/kg [14C]‐BIA 10‐2474. The calculated apparent terminal half‐life of total radioactivity was 45h. Five days after oral dosing of Wistar rats, 97.6% (94% to 103%) of the administered dose had been excreted, with 65.2% (58.7% to 73.8%) of the radiolabelled material excreted in urine and 23.7% (20.8% to 29.1%) excreted in faeces. The amount of BIA 10‐2474 excreted in exhaled air was less than 0.4 %. The majority of the faecal excretion occurred in the first 24h post‐dose, representing about 83.1% of the excretion via this route. Similarly, the majority of urinary radioactivity was excreted in the first 24 h post‐dose representing at least 93.0% of the excretion via this route. The quantitative Whole‐Body Autoradiography (QWBA) studies in rat following single oral administration of [14C]‐BIA 10‐2474 (30 mg/kg), indicate that radioactivity was rapidly absorbed and distributed throughout the body. The high tissue to blood ratio of total radioactivity observed in the kidney medulla (9.46), pituitary gland (6.32), liver (5.70), kidney cortex (4.83), spleen (4.02), thymus (3.94), epididymis (3.81) and skeletal muscle (3.63) at 24 h post‐dose suggests a slower elimination of BIA 10‐2474 related radioactivity from these tissues. Following oral administration of 90 mg/kg [14C]‐BIA 10‐2474, the hydroxylation of the cyclohexyl ring of BIA 10‐2474 (BIA 10‐3827 and BIA 10‐2639), the N‐oxide reduced form of BIA 10‐2474 (BIA 10‐2445) followed by the hydroxylation in the cyclohexyl ring (BIA 10‐3764 and/or BIA 10‐2631) were identified. In brain homogenate samples, BIA 10‐2474, and metabolites BIA 10‐3764 and/or BIA 10‐2631, and BIA 10‐2445 have been identified.In conclusion, BIA 10‐2474 was found to be rapidly absorbed and primarily excreted via the urine in the rat. The hydroxylation of the cyclohexyl ring of BIA 10‐2474 and BIA 10‐2445 was identified as the main metabolic route in the rat.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.