Phoenix version 7

GHB concentrations in tissue were corrected for residual blood volumes using Eq. 1 (31 (link)) where C′_GHB(t) is the measured tissue concentration, C_GHB(B) is the blood GHB concentration, and V_F is the volume fraction of residual blood or tissue. Tissue-specific residual blood volumes were obtained from Triplett et al. (32 (link)); testis residual blood volume was unavailable so the residual blood volume for brain was utilized. Area under the curve (AUC_{0 – inf}) values for plasma and tissues were calculated using the log/linear trapezoidal method with variability calculated by the Bailer method in WinNonLin version 5.2 (Pharsight Corp., Mountain View, CA) or the Bailer-Satterthwaite approximation in Phoenix version 7.0 (Certara). Time-averaged plasma and blood clearance were calculated as Dose/AUC. Tissue partitioning was calculated by the AUC method (K_p = AUC_tissue / AUC_plasma). Partitioning into the liver was corrected for metabolism based on in vivo Cl_int determined from steady-state infusions of GHB (14 (link)). Variability in tissue partitioning was calculated by the method of propagation of errors. Data was analyzed using one-way ANOVA with a Tukey’s post hoc test or unpaired t tests in GraphPad Prism version 6.0 (GraphPad Inc., San Diego, CA).

Pharmacokinetic parameters of 2-PMPA were analyzed using noncompartmental analysis method as implemented in the computer software program Phoenix version 7.0 (Certara Inc., Princeton, NJ). The maximum plasma concentration (C_max) and time to C_max (T_max) were the observed values. The area under the plasma concentration–time curve value was calculated to the last quantifiable sample (AUC_last) by use of the log-linear trapezoidal rule. The brain to plasma ratios were calculated as a ratio of mean AUCs (AUC_0−t,brain/AUC_0−t,plasma).