RT Journal Article
SR Electronic
T1 An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2162
OP 2173
DO 10.1124/dmd.112.046391
VO 40
IS 11
A1 Angela C. Doran
A1 Sarah M. Osgood
A1 Jessica Y. Mancuso
A1 Christopher L. Shaffer
YR 2012
UL http://dmd.aspetjournals.org/content/40/11/2162.abstract
AB Previous publications suggest that interstitial fluid compound concentrations (CISF) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal CISF remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (Cb,u/Cp,u) to project accurately dog and nonhuman primate (nhp) Cb,u, a CISF surrogate, from measured Cp,u for the highly permeable non-P-glycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-157119) and the P-glycoprotein substrates risperidone and 9-hydroxyrisperidone. First, in rats, it was determined for eight of nine commercial compounds that their single-dose-derived Cb,u/Cp,u were ≤2.5-fold different from their steady-state values; for all nine drugs, their Cb,u/Cp,u were ≤2.5-fold different from their steady-state CISF/Cp,u (Drug Metab Dispos 37:787–793, 2009). Subsequently, PF-4778574, CE-157119 and risperidone underwent rat, dog, and nhp neuropharmacokinetics studies. In large animals at each measured Cp,u, the methodology adequately predicted [estimated mean (95% confidence interval) of 1.02 (0.80, 1.29)] the observed Cb,u for PF-4778574 and CE-157119 but underpredicted [0.17 (0.12, 0.22)] Cb,u for risperidone and 9-hydroxyrisperidone. The data imply that forecasting higher species Cb,u from a measured Cp,u and rat acute dose-determined Cb,u:Cp,u is of high confidence for nonefflux transporter substrates that show net passive diffusion (PF-4778574) or net active influx (CE-157119) at the blood-brain barrier in rats. However, this methodology appears ineffective for correctly predicting large animal Cb,u for P-glycoprotein substrates (risperidone and 9-hydroxyrisperidone) because of their apparently much greater Cp,u-favoring Cb,u:Cp,u asymmetry in rats versus dogs or nhp. Instead, for such P-glycoprotein substrates, large animal-specific cerebrospinal fluid compound concentrations (CCSF) seemingly best represent Cb,u.