Table 1.
Parameter values used for the rosuvastatin simulations
| Parameter | Value | Reference/comments |
|---|---|---|
| Molecular weight (g/mol) | 481.54 | |
| fu—experimental | 0.107 | [8, 43] |
| Blood-to-plasma ratio (B:P)—experimental | 0.625 | [8, 43] |
| Log of the octanol:water partition coefficient (logP o:w)—experimental | 2.4 | [44] |
| Compound type | Monoprotic acid | Marvin Sketch 5.4.0.1 |
| pKa | 4.27 | [43, 45] |
| Main plasma binding protein | HSA (human serum albumin) | |
| Absorption | ||
| Model | ADAM | |
| Caco-2 permeability [P app,caco-2(7.4:7.4) (10−6 cm/s)] | 3.395 | [46] |
| Reference compound | Propranolol | |
| Reference P app,caco-2(7.4:7.4) (10−6 cm/s) | 20 | [46] |
| fa—predicted | 0.66 | Based on Caco-2 data |
| fa—observed | 0.55 | [8] |
| k a (h−1)—predicted | 0.35 | Based on Caco-2 data |
| k a (h−1)—observed | 0.46–0.78 | Range [20, 47] |
| Distribution | ||
| Model | Full PBPK | |
| V ss (L/kg)—predicted | 0.227 | Rodgers and Rowland method; see text for details |
| V ss (L/kg)—observed | 1.73 | [8] |
| Elimination | ||
| CLiv (L/h) | 48.78 | [8] |
| CLint (μL/min/mg protein) | 17 | Calculated using the retrograde model |
| CLR (L/h) | 17 | Meta-analysis [8, 48] |
| Transport (active and passive) | ||
| Intestinal efflux intrinsic clearance | ||
| CLint,T,BCRP (μL/min/cm2) | 35 | |
| Intestinal BCRP REF (User) | 1 | |
| Hepatic efflux intrinsic clearance | ||
| CLint,T,OATP1B1 (μL/min/million hepatocytes) | 109 | See text for details; [17] |
| Hepatic OATP1B1 REF (User) | 1 | |
| CLint,T,OATP1B3 (μL/min/million hepatocytes) | 36 | See text for details; [17] |
| Hepatic OATP1B3 REF (User) | 1 | |
| CLint,T,NTCP (μL/min/million hepatocytes) | 78 | See text for details; [17, 18] |
| Hepatic NTCP REF (User) | 1 | |
| CLint,T,BCRP (μL/min/million hepatocytes) | 1.23 | [49] |
| Hepatic BCRP REF (User) | 1 | |
| CLbile (L/h)—predicted | 15 | Using above data |
| CLbile (L/h)—observed | 4–195 | [15, 50] |
| Passive intrinsic clearance at sinusoidal membrane | ||
| CLint,PD (mL/min/million hepatocytes) | 0.0025 | [51] |
For CLR—these data were obtained from a meta-analysis of clinical data. The cited value is the weighted mean (accounting for the number of subjects in each study) of the reported values
Values in bold were refined using in vivo information
ADAM Advanced Dissolution, Absorption and Metabolism, BCRP breast cancer resistance protein, CL bile biliary clearance, CL int human liver microsome intrinsic clearance, CL int,PD passive diffusion parameter, CL iv in vivo systemic clearance, CL R renal clearance, fa fraction absorbed, fu fraction unbound in plasma, k a absorption rate constant, OATP organic-anion transporting polypeptide, NTCP sodium-dependent taurocholate co-transporting polypeptide, REF relative expression factor, V ss volume of distribution at steady state