title: Metabolism and Disposition of Pacritinib (SB1518), an Orally Active Janus Kinase 2 Inhibitor in Preclinical Species and Humans.
abstract: The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and in vivo in preclinical species and humans. Pacritinib showed ~5 fold higher affinity to human plasma proteins relative to mouse in vitro. It was metabolized by human CYP3A4 in vitro, and did not significantly induce CYP3A and 1A2 in human hepatocytes. In vitro metabolism studies with mouse and human liver microsomes showed the presence of four major metabolites of Pacritinib -M1 (oxidation), M2 (dealkylation), M3 (oxidation), M4 (reduction). The in vitro and in vivo metabolic patterns observed in mice and humans were in good agreement. Qualitatively and quantitatively, none of the metabolites formed in vivo was >10% of Pacritinib in mouse, dog and humans. Pacritinib showed systemic clearance of 8.0, 1.6, 1.6 l/h/kg, volume of distribution of 14.2, 7.9, 8.5 l/kg, t1/2 of 5.6, 6.0, 4.6 h, and oral bioavailability of 39, 10, and 24% in mouse, rat and dog, respectively. In radiolabeled mass balance and QWBA studies in mice, ~91% of the dose was recovered in feces, suggesting biliary clearance, and maximum radioactivity was seen in the gastrointestinal tract followed by the kidney, heart and low activity in the brain. The relatively high exposures of Pacritinib in humans might be attributed to its very high plasma protein binding, low metabolic and/or biliary clearance.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Mohammed Khalid
authors.initials: MK
authors.lastname: Pasha
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
authors.forename: Kee Cee
authors.initials: KC
authors.lastname: Goh
authors.affiliation: S*BIO Pte Ltd, 250 North Bridge Road, #28-00 Raffles City Tower, Singapore 179101. kantharaj.ethirajulu@gmail.com.
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D001952:Bridged-Ring Compounds / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003640:Dealkylation; D004285:Dogs; D005243:Feces / Q000737:chemistry; D065669:Hepatobiliary Elimination; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: C561234:11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene; D001952:Bridged-Ring Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2