Pharmacokinetics Studies Of Selective PDE10A Inhibitor PR-1346, As A Novel Therapy For Schizophrenia

Objective: PDE10A selective inhibitor may represent a new therapeutic approach to thetreatment of schizophrenia. It is highly effective for positive, negative symptoms andcognitive symptoms of schizophrenia in preclinical pharmacology studies. This study wasdesigned to explore the preclinical pharmacokinetic properties of PR-1346, a potentialnovel inhibitor of PDE10A.Methods:1) The metabolic stability of PR-1346in human, rat and mouse livermicrosomes.2) The CYPs inhibition of PR-1346(CYP3A4, CYP1A2, CYP2C9,CYP2C19and CYP2D6).3) The plasma protein binding of PR-1346(equilibrium dialysis).4) Permeability and P-gp efflux study of PR-1346in Caco-2and MDCKII-hMDR1cells.5)Pharmacokinetic study and brain distribution of PR-1346post i.v. and p.o. administrationin CD-1mice.Results:1) The intrinsic clearance of PR-1346in human, rat and mouse liver microsomeswas0.252mL/minute/kg,3.808mL/minute/kg,42.63mL/minute/kg, respectively.2)PR-1346(10μM) displayed inhibitory effects against CYP2C9，CYP2C19and CYP2D6with inhibition79.3%,90.4%and52.5%, but not against CYP3A4and CYP1A2.3) Theplasma protein binding of PR-1346(1μM) in human, rat and mouse plasma protein weremore than99%, and no significant species difference.4) For Caco-2transport, the Papp ofA->B and B->A of PR-1346were1.46*10-6cm/s and4.66*10-6cm/s, with an effluxratio of3.0. For MDCKII-hMDR1transport, the Papp of A->B and B->A of PR-1346were0.96x10-6cm/s and1.49x10-6cm/s, with an efflux ratio of1.17.5) For thepharmacokinetic study of PR-1346post p.o. administration (2mg/kg) in CD-1mice, thet1/2was8.8hours, the Cmaxwas974.3ng/mL, the AUC as1178.9ng/mL*hour, the clearance (CL) was6.1ng/mL/kg and the bioavailability was87.4%. High concentrationsof PR-1346were found in the brain with a Tmaxof2hours, which lasted for8hours(244.1~528.8ng/mL) and reached detection limit after24hours.Conclusion：PR-1346was stable in human, rat and mouse liver microsomes; PR-1346(10μM) had inhibitory effects to the activities of CYP2C9, CYP2C19and CYP2D6, but not toCYP3A4and CYP1A2; PR-1346displayed low permeability and moderate efflux inbi-directional transport study, and high plasma protein binding; The pharmacokineticparameters of PR-1346post p.o. administration in CD-1mice, such as t1/2, Cmax, AUC, CLand brain distribution were excellent. Taken together, the novel PDE10A selective inhibitorPR-1346has good drug-like properties, which may be a promising candidate for thetreatment of schizophrenia.