TABLE 2

Parameters with fixed values in the described bosentan PBPK model

ParameterValueSourceParameterValueSource
pKa5.2 (acidic)In housekon (1/nM/h)3600Alberty and Hammes (1958)
logD7.41.3In housekoff,plasma (h−1)8.18 × 107Supplemental Material
MW (g/mol)551.6In housekoff,RBC (h−1)1.25 × 107Supplemental Material
KM,liver,uptake (nM)4343SCHHkoff,liver,tissue (h−1)4.80 × 107SCHH
KM,liver,metabolism (nM)6.9 × 104Shen et al. (2009)Binding site in plasma (nM)1.14 × 106Supplemental Material
KM,enterocyte,metabolism (nM)6.9 × 104Shen et al. (2009)Binding site in RBCs (nM)4.11 × 104Supplemental Material
Ratio of kenterocyte,metabolism to kliver,metabolism0.0260Supplemental MaterialBinding site liver tissue (nM)3.67 × 105SCHH
Fa, 62.5-mg tablet0.973Supplemental MaterialCLsystemic,blood,pass (l/h)1.12 × 103Supplemental Material
Fa, 125-mg tablet1Supplemental MaterialCLliver,blood,pass (l/h)72.5Supplemental Material
Fa, 500-mg tablet0.823Supplemental MaterialCLvilli,blood,pass (l/h)2.43Supplemental Material
Fa, 125 mg high fat1Supplemental MaterialP450 kentercoyte,degradation (h−1)0.0300Yang et al. (2008)
Fa, 500 mg high fat1Supplemental MaterialP450 kliver,degradation (h−1)0.0250Quinney et al. (2010)
Human HCT0.519In houseInduction EC50 (nM)1000Hepatocyte induction assay
IC50,NTCP (nM)2.4 × 104Leslie et al. (2007)IC50,MRP3 (nM)4.2 × 104Morgan et al. (2013)
IC50,BSEP (nM)2.3 × 104Morgan et al. (2013)IC50,MRP4 (nM)2.2 × 104Morgan et al. (2013)
  • HCT, hematocrit; SCHH, sandwich cultured human hepatocyte.