Table S2Summary of the PBPK model drug input data for buprenorphine, ketoconazole and rifampin

Parameter / Buprenorphine / Ketoconazole / Rifampin
MW (g/mol) / 467.64 / 531.4 / 823
log P / 4.82 / 4.04 / 4.01
Compound type / Ampholyte / Diprotic Base / Ampholyte
pKa1 (acid), pKa2 (base) / 9.62; 8.31 / 2.94; 6.51 / 1.7; 7.9
B:P / 1 / 0.62 / 0.9
fu / 0.04 / 0.029 / 0.116
Vss (L/kg) / 2.7 / 0.345 / 0.42
Vsac (L/kg) / 1.3 / - / -
Kin (h-1) / 0.64 / - / -
Kout (h-1) / 0.07 / - / -
Caco-2 PappA-B 7.4:7.4 (10-6cm/s) / 66.7 / - / 15
PSA(Å2) / - / 69.06 / -
Proportion of dose inhaled / 20% / - / -
Proportion of dose swallowed / 80% / - / -
fa (Lung) / 1 / - / -
ka (h-1) (Lung) / 0.5 / - / -
fa (GI Tract) / 1 / 1 / 0.925
ka (h-1) (GI Tract) / 0.33 / 0.78 / 0.94
fuGut / 1 / 0.06 / 1
QGut (L/h) / 14.5 / 15.2 / 9.42
CLiv (L/h) / - / - / 8.7
CLpo (L/h) / - / 7.4 / -
CLint,u (µl/min per mg) / 889 / - / -
CYP3A4 / 472 / - / -
UGT1A1-population / 279 / - / -
UGT1A1-EM / 341 / - / -
CLRenal (L/h) / 0.535 / 0.147 / 1.26
Biliary clearance (µl/min per million cells) / 51 / - / -
Competitive Inhibition
CYP3A4 Ki (µM) / - / 0.015 / 15
fumic / - / 0.97 / 1
Induction/Suppression
CYP3A4 Ind Max / - / - / 16
MIA (pmol/mg microsomal protein) / - / - / 4018
Ind C50 (µM) / - / - / 0.32
fuinc / - / - / 1

fu, fraction unbound in plasma; Kin and Kout, rate constants into and out of the additional compartment; QGut, flow rate for overall delivery of drug to the gut enterocytes (depends on drug permeability and blood flow to villi); Vss, volume of distribution at steady-state; Vsac, volume of an additional compartment; MIA, maximum inducible abundance.