Summary of victim drug input parameters for PBPK modeling and simulations
| Parameters | Pioglitazonea | Rosiglitazoneb | Repaglinidec | Cerivastatina | Gemfibrozild | Gemfibrozil-1-O-β-Glucuronided |
|---|---|---|---|---|---|---|
| Physicochemical properties | ||||||
| Molecular weight (g/mol) | 356.4 | 357.4 | 452.6 | 459 | 250.3 | 426.5 |
| Log P | 3.5 | 2.6 | 4.87 | 1.8 | 4.3 | 3.3 |
| Compound type | Monoprotic base | Ampholyte | Ampholyte | Monoprotic acid | Monoprotic acid | Monoprotic acid |
| pKa | 5.53 | 6.25 and 6.32 | 4.19 and 5.78 | 5 | 4.75 | 2.68 |
| Fraction unbound | 0.015 | 0.002 | 0.015 | 0.013 | 0.008 | 0.115 |
| Blood/plasma ratio | 1 | 0.57 | 0.62 | 0.76 | 0.825 | 0.825 |
| Absorption | ||||||
| Absorption type | ADAM | 1st order | ADAM | ADAM | 1st order | |
| Fraction absorbed | 0.98 | 1 (Ka = 3.6 h−1) | 0.99 | 0.75 | 1 (Ka = 3 h−1) | |
| Caco-2 permeability (×10−6 cm/s) | 31 | 26.1 | 10 | |||
| Absorption scalar | 1.873 | 1.873 | ||||
| fuGut | 1 | 1 | 1 | 1 | 1 | 1 |
| Distribution | ||||||
| Distribution model | Minimal PBPK | Minimal PBPK | Full PBPK (method 2) | Full PBPK (method 2) (Kp scalar 1.5) | Minimal PBPK | Minimal PBPK |
| Vss (l/kg) | 0.253 | 0.12 | 0.256 | 0.31 | 0.08 | 0.1 |
| Elimination | ||||||
| CLint,CYP2C8 (µl/min/mg) | 27.5 (HLM) | 191 (HLM) | 93 (HLM) | 19.1 (HLM) | ||
| CLint,CYP3A4 (µl/min/mg) | 1.5 (HLM) | 38 (HLM) | 12.7 (HLM) | 0.29 (rCYP)e | ||
| CLint,others (µl/min/mg) | 6.1 (CYP2C19-HLM) | 102 (CYP2C9-HLM) | 65 (UGT2B7-HLM) | |||
| Biliary CLint (µl/min/10−6cells) | 5.2 | |||||
| Renal clearance (l/h) | 0.32 | |||||
| Hepatobiliary transport | ||||||
| Liver unbound fraction (Intra-/extracellular) | 0.143/0.028 | 0.97/0.025 | ||||
| Passive diffusion (µl/min/10−6cells) | 22 | 17.5 | ||||
| CLint,active (µl/min/10−6cells) | 35.5 | 16.8 | ||||
| Scaling factor (active uptake) | 18.7f | 30.5f | ||||
| References | (Jaakkola et al., 2006) | (Varma et al., 2013a) | (Muck et al., 1997; Varma et al., 2014) | (Varma et al., 2013a) | (Varma et al., 2013a) |
ADAM, advanced dissolution, absorption, and metabolism model; P, partition coefficient; pKa, acid dissociation constant.
↵a Models developed in this current study based on the literature in vitro data (pioglitazone) or in-house in vitro data (cerivastatin).
↵b Rosiglitazone model was adopted from Simcyp V13 compound files.
↵c Model adopted from a previous report (Barton et al., 2013).
↵d Model modified from a previous report (Barton et al., 2013).
↵e CLint,CYP3A4 in µl/min/pmol.
↵f Estimated by fitting to intravenous data. See Materials and Methods.