Pharmacokinetic data related to in vivo reach of circulating XueBiJing phthalides
The details of in vitro pharmacokinetic studies are described in the Supplemental Materials and Methods (Supportive In Vitro Characterizations of Phthalides). The quoted volumes of total body water, intracellular fluids, extracellular fluids, and plasma for a 70-kg man are 0.60, 0.34, 0.26, and 0.04 l/kg, respectively; whereas such volumes for a 0.25-kg rat are 0.67, 0.37, 0.30, and 0.03 l/kg, respectively (Davies and Morris, 1993). XueBiJing compounds with volume of distribution at steady state (VSS) in a human larger than 0.26 l/kg are predicted to have intracellular reach. Membrane permeability was determined based on apparent permeability coefficient (Papp) value of the compound measured on Caco-2 cell monolayers, with a Papp value < 0.2 × 10−6, 0.2 × 10−6–2.8 × 10−6, and > 2.8 × 10−6 cm/s indicating low, intermediate, and high membrane permeability, respectively (Li et al., 2012).
| Compound | VSS | Detection in Rat Brain | fu | Membrane Permeability, Caco-2 Cell-based Papp (EfR) | B/P Ratio | |||
|---|---|---|---|---|---|---|---|---|
| Human | Rat | Human (%) | Rat (%) | Human | Rat | |||
| l/kg | ||||||||
| Senkyunolide I (15) | 1.18 ± 0.17 | 2.19 ± 0.11 | Detected; KP, 1.8 | 53.6 | 48.3 | Good, 39.0 × 10−6 (1.2) | 0.69 | 0.82 |
| Senkyunolide G (12) | 0.09 ± 0.01 | 0.85 ± 0.10 | Not detected | 3.0 | 13.3 | Good, 27.8 × 10−6 (1.4) | 0.62 | 0.61 |
| Senkyunolide H (16) | 1.19 ± 0.12 | 2.02 ± 0.06 | Detected; KP, 1.0 | 49.8 | 48.1 | Good, 34.7 × 10−6 (1.3) | NM | 0.78 |
| Senkyunolide N (17) | 0.98 ± 0.26 | 1.18 ± 0.07 | Detected; KP, 1.4 | 76.0 | 74.6 | Good, 17.3 × 10−6 (1.4) | NM | 0.90 |
| 3-Hydroxy-3-n-butylphthalide (10) | 0.22 ± 0.04 | 0.64 ± 0.12 | Not detected | 17.9 | 18.1 | Good, 3.62 × 10−6 (2.4) | NM | 0.74 |
B/P ratio, blood-to-plasma concentration ratio; EfR, efflux ratio; fu, unbound fraction of compound in plasma; KP, AUC-based partition coefficient of compound between brain and plasma; NM, not measured.