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 142
OP 151
DO 10.1124/dmd.120.000242
VO 49
IS 2
A1 Keumhan Noh
A1 Alicia Pietrasiewicz
A1 Xingrong Liu
A1 Cong Wei
YR 2021
UL http://dmd.aspetjournals.org/content/49/2/142.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 after constant intravenous infusion, and pharmacokinetics (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 intravenous 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, 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 Kp,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 t1/2,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.Significance Statement We demonstrated that the extent of brain penetration and pharmacokinetic parameters (such as clearance, Vss, and effective t1/2) can be determined from a single constant intravenous infusion study in rats.