Metabonomic evaluation of metabolic dysregulation in rats induced by PF 376304, a novel inhibitor of phosphoinositide 3-kinase.

ABSTRACT

Phosphoinositide 3-kinase (PI3K) is an enzyme fundamental to the regulation of various metabolic processes. Metabonomic studies were undertaken in order to gain mechanistic insight into significant, yet unexplained, toxicity issues associated with PF 376304, a nonspecific PI3K inhibitor under development for anti-inflammatory indications. Two experiments were conducted in which rats were given daily doses of up to 1000 mg of PF 376304/kg for as long as 7 days. Mortality rapidly ensued (within 72 h) at doses of >or=300 mg/kg. Doses of >or=100 mg/kg were associated with a profound but transient glucosuria. Despite the magnitude of this effect, within 72 h urinary glucose excretion in surviving animals returned to control levels even with continued dosing. Other metabolic effects associated with drug treatment included increased urinary beta-hydroxybutyrate and creatine and decreased citrate. A time-course study revealed elevated serum glucose within 1 h, followed by increases in serum insulin and decreases in serum triglycerides. Serum corticosterone was also significantly elevated within 1 h of treatment. All metabolic effects were largely reversed within 24 h of administration of the third daily dose and remained that way through day 7. The likely explanation for the onset of effects involves the role of PI3K in regulation of glucose at multiple points, but the reversal of the effects in the presence of continued exposure to the drug has not been explained. Finally, the data demonstrate the power of metabonomics technology in mechanistic toxicology investigations.