Summary of input parameters for repaglinide dynamic and static mechanistic models
| Parameters | Repaglinide | Source | Rifampicind | Source |
|---|---|---|---|---|
| Physicochemical properties | ||||
| Molecular weight (g/mol) | 452.6 | ACD | 823 | |
| log P | 4.87 | ACD | 3.28 | |
| Compound type | Ampholyte | ACD | Ampholyte | |
| pKa | 4.19, 5.78 | ACD | 1.7, 7.9 | |
| Fraction unbound | 0.015 | (Plum et al., 2000) | 0.15 | |
| Blood/plasma ratio | 0.62 | (Kajosaari et al., 2005a) | 0.90 | |
| Absorption | ||||
| Absorption type | ADAM | First-order | ||
| Fraction absorbed | >0.95 | (Hatorp et al., 1998; Varma et al., 2010) | 1.0 | |
| Caco-2 permeability (×10−6 cm/s) | 26.1 | In-house data | ||
| Absorption scalar | 1.873 | In-house data | ||
| Ka | 0.51 | |||
| fugut | 1 | Assumed | 0.15 | |
| Distribution | ||||
| Distribution model | Whole-body PBPK | (Rodgers et al.; Rodgers and Rowland, 2006) | Minimal PBPK | |
| Elimination | ||||
| Intravenous clearance (l/h) | 32.6 | (Hatorp et al., 1998) | 7.0 | |
| In vivo CLint,h (ml/min/kg) | 1326b | (Hatorp et al., 1998) | ||
| CLint,CYP2C8 (µl/min/mg-microsomal protein) | 93c | (Kajosaari et al., 2005a) | ||
| CLint,CYP3A4 (µl/min/mg-microsomal protein) | 38c | (Kajosaari et al., 2005a) | ||
| Renal elimination (%) | <1% | (Hatorp et al., 1998) | ||
| Hepatobiliary transport | ||||
| Liver unbound fraction (Intra-/extracellular) | 0.143/0 .028 | Calculated | ||
| PSpd (µl/min/10−6cells) | 24 | SCHH data (Varma et al., 2013) | ||
| PSinflux,active (µl/min/10−6cells) | 37 | SCHH data (Varma et al., 2013) | ||
| Scaling factor (active) for dynamic model | 16.9 | Estimateda (Varma et al., 2013) | ||
| Scaling factor (active) for static model | 18.5 | Estimateda | ||
| CLint,bile (µl/min/10−6cells) | 0 | SCHH data (Varma et al., 2013) | ||
| Rifampicin interaction potency | ||||
| CYP3A4 Emax | 49.5 | In-house data | ||
| CYP3A4 EC50 (µM) | 0.228 | In-house data | ||
| CYP3A4 Ki (µM) | 18.5 | (Kajosaari et al., 2005a) | ||
| CYP2C8 Ki (µM) | 30.2 | (Kajosaari et al., 2005a) | ||
| OATP1B1 Ki (µM) | 0.93 | (Varma et al., 2012b) |
ACD, Advanced Chemistry Development (ACD/Laboratories, Toronto, ON) software version 11.02 (SciFinder 2007.1); ADAM, advanced dissolution, absorption, and metabolism model; fu,gut, fraction unbound in the gut; P, partition coefficient; pKa, acid dissociation constant; PSpd, passive diffusion intrinsic clearance; PSinflux,active, sinusoidal active uptake; SCHH, sandwich-cultured human hepatocyte.
↵a Estimated by fitting to intravenous pharmacokinetics data (PBPK model) or in vivo CLint,h (static model). See Materials and Methods.
↵b CLint,h from intravenous hepatic blood clearance (CLh) was calculated using CLint,h = CLh/[fu,b × (1−CLh/Qh)].
↵c In vitro fmCYP3A4 equaling to 0.29.
↵d Input parameters were directly adopted from compound files of the Simcyp compound library.