RT Journal Article SR Electronic T1 Use of Intravenous Infusion Study Design to Simultaneously Determine Brain Penetration and Systemic Pharmacokinetic Parameters in Rats JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP DMD-AR-2020-000242 DO 10.1124/dmd.120.000242 A1 Keumhan Noh A1 Alicia Pietrasiewicz A1 Xingrong Liu A1 Cong Wei YR 2020 UL http://dmd.aspetjournals.org/content/early/2020/12/01/dmd.120.000242.abstract AB In drug discovery, the extent of brain penetration as measured by free brain/plasma concentration ratio (Kp,uu) is normally determined from one experiment following constant intravenous (IV) infusion, and PK parameters including clearance (CL), volume of distribution at steady-state (VSS), and effective half-life (t1/2,eff) are determined from another experiment after a single IV-bolus injection. The objective of the present study was to develop and verify a method to simultaneously determine Kp,uu and PK parameters from a single intravenous infusion experiment. In this study, 9 compounds (atenolol, loperamide, minoxidil, NFPS, sulpiride, and 4 proprietary compounds) were intravenously infused for 4 h at 1 mg/kg or 24 h at 1 or 6 mg/kg or bolus injection at 1 mg/kg. Plasma samples were serially collected and brain and CSF samples were collected at the end of infusion. The PK parameters were obtained using non-compartmental (NCA) and compartmental analyses. The Kp,uu ,brain values of those compounds increased up to 2.86-fold from 4 h to 24 h. The CL calculated from infusion rate vs. steady-state concentration from the 24 h infusion studies was more consistent with the CL from the IV bolus studies than that from 4 h infusion studies (CL average fold-of-difference 1.19~1.44 vs. 2.10). The compartmental analysis using 1- and 2-compartment models demonstrated better performance than NCA regardless of study design. In addition, Vss and t1/2,eff could be accurately obtained by 1-compartment analysis within 2-fold difference. In conclusion, both Kp,uu,brain and PK parameters can be successfully estimated from a 24 h IV-infusion study design. Significance Statement We demonstrated that the extent of brain penetration and pharmacokinetic parameters (such as CL, Vss and t1/2,effect) can be determined from a single constant IV infusion study in rats.