Abstract

In drug discovery, the extent of brain penetration as measured by free brain/plasma concentration ratio (K_p,uu) is normally determined from one experiment after constant intravenous infusion, and pharmacokinetics (PK) parameters, including clearance (CL), volume of distribution at steady state (Vss), and effective half-life (t_1/2,eff) are determined from another experiment after a single intravenous bolus injection. The objective of the present study was to develop and verify a method to simultaneously determine K_p,uu and PK parameters from a single intravenous infusion experiment. In this study, nine compounds (atenolol, loperamide, minoxidil, N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine, sulpiride, and four proprietary compounds) were intravenously infused for 4 hours at 1 mg/kg or 24 hours at 1 or 6 mg/kg or bolus injected at 1 mg/kg. Plasma samples were serially collected, and brain and cerebrospinal fluid samples were collected at the end of infusion. The PK parameters were obtained using noncompartmental analysis (NCA) and compartmental analysis. The K_p,uu,brain values of those compounds increased up to 2.86-fold from 4 to 24 hours. The CL calculated from infusion rate over steady-state concentration from the 24-hour infusion studies was more consistent with the CL from the intravenous bolus studies than that from 4-hour infusion studies (CL avg. fold of difference 1.19–1.44 vs. 2.10). The compartmental analysis using one- and two-compartment models demonstrated better performance than NCA regardless of study design. In addition, volume of distribution at steady state and t_1/2,eff could be accurately obtained by one-compartment analysis within 2-fold difference. In conclusion, both unbound brain-to-plasma ratio and PK parameters can be successfully estimated from a 24-hour intravenous infusion study design.