Article Figures & Data
Tables
Compounds Dose (mg/kg/h) Dosing Vehicle Cerivastatin 0.10 Saline Fluvastatin 0.10 12% (w/v) SBECD in water Rosuvastatin 0.10 12% (w/v) SBECD in water Pravastatin 0.10 12% (w/v) SBECD in water PF-04991532 0.12 PBS, pH 7.4 PF-05187965 1.2 12% (w/v) SBECD in water with 3 M equivalent 1N HCl SBECD, sulfobutylether-β-cyclodextrin.
Compounds Plasma Concentration at Terminal Time Point (ng/ml) Liver Concentration at Terminal Time Point (ng/ml) Total Liver-to-Plasma Ratio (Kp) Rat Plasma fu,p Rat Liver fu,liver In Vivo Rat Liver-to-Plasma Kpuu Cerivastatin 261 ± 70 6717 ± 960 27 ± 8.0 0.016 ± 0.001 0.017 ± 0.001 29 ± 8.5 Fluvastatin 245 ± 34 8990 ± 1490 37 ± 7.4 0.011 ± 0.001 0.013 ± 0.001 44 ± 8.7 Rosuvastatin 14 ± 3.7 178 ± 50 13 ± 2.2 0.044 ± 0.009 0.19 ± 0.02 57 ± 9.5 Pravastatin 33 ± 19 171 ± 15 6.7 ± 4.5 0.54 ± 0.02 0.18 ± 0.02 2.2 ± 1.5 PF-04991532 172 ± 67 1170 ± 364 7.1 ± 2.0 0.12 ± 0.01 0.096 ± 0.02 5.7 ± 1.6 PF-05187965 76 ± 21 323 ± 13 4.4 ± 1.0 0.27 ± 0.01 0.15 ± 0.02 2.4 ± 0.57 Compounds fu,media fu,cella Kp Kpuu Cerivastatin 0.022 ± 0.003 0.017 ± 0.001 27 ± 2.6 21 ± 2.0 Fluvastatin 0.016 ± 0.001 0.013 ± 0.001 27 ± 1.8 22 ± 1.5 Rosuvastatin 0.19 ± 0.02 0.19 ± 0.02 35 ± 0.6 35 ± 0.6 Pravastatin 0.49 ± 0.06 0.18 ± 0.02 8.3 ± 0.8 3.0 ± 0.3 PF-04991532 0.12 ± 0.01 0.096 ± 0.02 8.9 ± 0.1 7.1 ± 0.1 PF-05187965 0.36 ± 0.01 0.15 ± 0.02 10 ± 0.4 4.2 ± 0.2 ↵a Fu,cell is assumed to be the same as fu,liver in Table 2, because 80% of the liver is made of hepatocytes by volume (Bayliss and Skett, 1996).
- TABLE 4
Correlation between in vivo rat liver-to-plasma Kpuu and in vitro suspension rat hepatocyte Kpuu
Compounds Papp MDCK-LE (10−6 cm/s)a In Vivo Rat Liver-to-Plasma Kpuu In Vitro Suspension Rat Hepatocyte Kpuu Fold Difference in Vivo Kpuu/In Vitro Kpuu Cerivastatin 10.3 29 ± 8.5 21 ± 2.0 1.4 Fluvastatin 7.8 44 ± 8.7 21 ± 1.5 2.1 Rosuvastatin 0.9 57 ± 9.5 35 ± 0.6 1.6 Pravastatin 0.4 2.2 ± 1.5 2.9 ± 0.3 0.8 PF-04991532 1.0 5.7 ± 1.6 7.1 ± 0.1 0.8 PF-05187965 0.5 2.4 ± 0.6 4.2 ± 0.2 0.6 MDCK-LE, Madin-Darby Canine Kidney-low efflux cell line; Papp, apparent permeability.
↵a Papp was measured using the MDCK-LE method (Di et al., 2011), and the values were obtained from the following references: Pfefferkorn et al. (2012), Stevens et al. (2013), and Varma et al. (2015).
Additional Files
Data Supplement
Files in this Data Supplement:
- Supplemental Data -
Supplemental Figure 1 - Plasma mevalonic acid (MVA) profiles in response to rosuvastatin
Supplemental Figure 2 - Plasma mevalonic acid (MVA) profiles in response to pravastatin
Supplemental Table 1 - Model Parameters of Rosuvastatin PK/PD modeling
Supplemental Table 2 - Model Parameters of Pravastatin PK/PD modeling
- Supplemental Data -
