Absorption, metabolism and excretion of pictilisib, a potent pan-class I phosphatidylinositol-3-Kinase (PI3K) inhibitor, in rats, dogs, and humans
Creators: name: Yue, Qin
name: Khojasteh, S. Cyrus
name: Cho, Sungjoon
name: Ma, Shuguang
name: Mulder, Teresa
name: Chen, John
name: Pang, Jodie
name: Ding, Xiao
name: Deese, Alan
name: Pellet, Jackson D.
name: Siebers, Nicholas
name: Joas, Lori
name: Salphati, Laurent
name: Ware, Joseph A.
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biophysics
subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Physiology
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Ecology
subject: Marine Biology
subject: Cancer
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: Computational Biology

description: The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [<sup>14</sup>C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively.Pictilisib was rapidly absorbed with T<sub>max</sub> less than 2 h across species. In systemic circulation, pictilisib represented the predominant total radioactivity greater than 86.6% in all species.Total pictilisib and related radioactivity was recovered from urine and faeces in rats, dogs, and human at 98%, 80% and 95%, respectively, with less than 2% excreted in urine and the rest excreted into faeces.In rat and dog, more than 40% of drug-related radioactivity was excreted into the bile suggesting biliary excretion was the major route of excretion. Unchanged pictilisib was a minor component in rat and dog bile. The major metabolite in bile was <i>O</i>-glucuronide of oxidation on indazole moiety (M20, 21% of the dose) in rats and an oxidative piperazinyl ring-opened metabolite M7 (10.8% of the dose) in dogs.Oxidative glutathione (GSH) conjugates (M18, M19) were novel metabolites detected in rat bile, suggesting the potential generation of reactive intermediates from pictilisib. The structure of M18 was further confirmed by NMR to be a <i>N</i>-hydroxylated and GSH conjugated metabolite on the moiety of the indazole ring. The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [<sup>14</sup>C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively. Pictilisib was rapidly absorbed with T<sub>max</sub> less than 2 h across species. In systemic circulation, pictilisib represented the predominant total radioactivity greater than 86.6% in all species. Total pictilisib and related radioactivity was recovered from urine and faeces in rats, dogs, and human at 98%, 80% and 95%, respectively, with less than 2% excreted in urine and the rest excreted into faeces. In rat and dog, more than 40% of drug-related radioactivity was excreted into the bile suggesting biliary excretion was the major route of excretion. Unchanged pictilisib was a minor component in rat and dog bile. The major metabolite in bile was <i>O</i>-glucuronide of oxidation on indazole moiety (M20, 21% of the dose) in rats and an oxidative piperazinyl ring-opened metabolite M7 (10.8% of the dose) in dogs. Oxidative glutathione (GSH) conjugates (M18, M19) were novel metabolites detected in rat bile, suggesting the potential generation of reactive intermediates from pictilisib. The structure of M18 was further confirmed by NMR to be a <i>N</i>-hydroxylated and GSH conjugated metabolite on the moiety of the indazole ring.