Summary of input parameters for repaglinide dynamic and static mechanistic models

Physicochemical properties
 Molecular weight (g/mol)452.6ACD823
 log P4.87ACD3.28
 Compound typeAmpholyteACDAmpholyte
 pKa4.19, 5.78ACD1.7, 7.9
 Fraction unbound0.015(Plum et al., 2000)0.15
 Blood/plasma ratio0.62(Kajosaari et al., 2005a)0.90
 Absorption typeADAMFirst-order
 Fraction absorbed>0.95(Hatorp et al., 1998; Varma et al., 2010)1.0
 Caco-2 permeability (×10−6 cm/s)26.1In-house data
 Absorption scalar1.873In-house data
 Distribution modelWhole-body PBPK(Rodgers et al.; Rodgers and Rowland, 2006)Minimal PBPK
 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 .028Calculated
 PSpd (µl/min/10−6cells)24SCHH data (Varma et al., 2013)
 PSinflux,active (µl/min/10−6cells)37SCHH data (Varma et al., 2013)
 Scaling factor (active) for dynamic model16.9Estimateda (Varma et al., 2013)
 Scaling factor (active) for static model18.5Estimateda
 CLint,bile (µl/min/10−6cells)0SCHH data (Varma et al., 2013)
Rifampicin interaction potency
 CYP3A4 Emax49.5In-house data
 CYP3A4 EC50 (µM)0.228In-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.