TABLE 1.

Summary of fixed or initial parameters for rifampicin, digoxin, talinolol, and quinidine

Parameter	Rifampicin 15	Digoxin	Talinolol	Quinidine
T lag (h)	0.255	0	0	0
k stomach (/h)	–	–	0.8 a	5 a
R B	0.9	0.955 44	0.941 22	0.919 22
f B	0.0778	0.785 b	0.478 b	0.218 b
f hepatocytes	0.0814	0.535 c	0.893 c	–
f enterocytes	0.115	0.360 c	0.724 22	0.215 22
f renal cell	–	0.504 c	0.881 c	0.856 c
SFKp	6.65	30 a	2 a	5 a
K p,liver c	–	–	–	0.409
K p,muscle c	0.0947	–	0.861	0.434
K p,skin c	0.326	–	0.877	0.589
K p,adipose c	0.0629	–	0.383	0.229
K p,serosa c	0.200	1.25	0.908	0.523
f BCLint,all or f BCLint (L/h/kg)	0.251	0.0091 d	0.6 a	0.189 a , d
R dif,inf,liver	0.129	0.665 26	1 e	–
β liver	0.2	0.2/0.5/0.8	0.2/0.5/0.8	–
γ inf,liver	0.778	1	4.15 45	–
f bile	–	0.77 7	0.914 46	–
f m,liver or f P‐gp,liver	0.759 (UGT)	1 (P‐gp) e	1 (P‐gp) e	0.962 (CYP3A) f
PSdif,gut lumen to enterocytes (L/h/kg)	0.08 g	0.01 a	0.016 h	0.011 h
R dif,eff,duodenum i	–	1.45	1.05	1.38
R dif,eff,jejunum i	–	0.406	0.292	0.385
R dif,eff,ileum i	–	0.332	0.239	0.315
γ inf,enterocytes j	0.778	1 e	1 e	1 e
CLint,met,enterocytes (L/h/kg)	0.005 g	0 i	0 i	0.008 h
f m,enterocytes or f P‐gp,enterocytes	0.759 (UGT)	1 (P‐gp) e	1 (P‐gp) e	1 (P‐gp) e 1 (CYP3A) e
R dif,inf,kidney	–	0.002 a	0.012 k	0.02 k
R dif,eff,kidney	–	1 k	1 k	0.3 k
PSdif,proximal cells to vessels (L/h/kg) l	–	0.00125	0.000617	0.0104
PSdif,proximal cells to tubule (L/h/kg) l	–	0.00941	0.00464	0.0784
PSdif,distal cells to vessels (L/h/kg) l , m	–	0.000324	0.00016	0.0027
PSdif,collecting duct cells to vessels (L/h/kg) l , n	–	0.0000694	0.0000343	0.000579
f P‐gp,kidney	–	1 (P‐gp) e	1 (P‐gp) e	1 (P‐gp) e
K m,u (ng/mL)	146 (OATP1B)	–	4071 (P‐gp) 22	409 (P‐gp) 22 1996 (CYP3A) 22

Note: Physiologically based pharmacokinetic model parameters of rifampicin were mostly adapted from the previous report. ¹⁵ The following parameters were also used: rifampicin parameters—CL_renal (0.011 L/h/kg), E _max,UGT (1.34, autoinduction), E _max,CYP3A (4.57), EC_{50 ,u} (63.9 nmol/L); Digoxin parameters—f _muscle (0.716),^c f _skin (0.187),^c f _adipose (0.00854),^c PS_{tissue ,in} (0.3 L/h/kg),^a PS_tissue,ratio (5)^a; talinolol parameterso—R _{dif,inf,gut lumen to enterocytes} (0.5),^e γ _{inf,proximal cells} (8.95), γ _{inf,distal cells} (7.01), γ _{inf,collecting duct cells} (8.95), γ _{eff,proximal cells} (8.04), γ _{eff,distal cells} (5.07), γ _{eff,collecting duct cells} (2.72); quinidine parameterso—SF_{renal permeability} (0.1), γ _{inf,proximal cells} (7.22), γ _{inf,distal cells} (5.96), γ _{inf,collecting duct cells} (7.22), γ _{eff,proximal cells} (6.41), γ _{eff,distal cells} (4.35), γ _{eff,collecting duct cells} (2.50).

Abbreviations: β _liver, (CL_int,met + CL_int,bile)/(PS_dif,eff + CL_int,met + CL_int,bile); CL_int, hepatic intrinsic clearance; CL_int,all, overall hepatic intrinsic clearance; CL_int,bile, intrinsic clearance of biliary excretion; CL_int,met, intrinsic clearance of metabolism; CL_renal, renal clearance; CYP3A, cytochrome P450 3A; EC_50,u, unbound concentration for half maximum induction effect; E _max, maximum induction effect; f, unbound fraction in each tissue; F _a(F _g), intestinal availability after an oral dose; f _B, unbound fraction in blood; f _bile, CL_int,bile/(CL_int,bile + CL_int,met); f _m, fractional metabolism of each metabolizing enzyme to overall metabolism: f _P‐gp, fractional efflux of P‐gp to overall transpoter efflux; γ _eff, PS_dif,inf/PS_dif,eff on apical membrane; γ _inf, PS_dif,inf/PS_dif,eff on sinusoidal or basolateral membrane; K _m,u, unbound Michaelis–Menten constant; K _p, tissue/blood concentration ratio; k _stomach, transit rate constant from stomach to duodenum lumen; OATP1B, organic anion transporting polypeptide 1B; P‐gp, P‐glycoprotein; PS_act,inf, influx intrinsic clearance by transporter; PS_{dif,collecting duct cells to vessels}, intrinsic clearance by passive diffusion from collecting duct cells to vessels; PS_{dif,distal cells to vessels}, intrinsic clearance by passive diffusion from distal cells to vessels; PS_dif,eff, efflux intrinsic clearance by passive diffusion; PS_{dif,gut lumen to enterocytes}, intrinsic clearance by passive diffusion from gut lumen to enterocytes; PS_dif,inf, influx intrinsic clearance by passive diffusion; PS_{dif,proximal cells to tuble}, intrinsic clearance by passive diffusion from proximal cells to tuble; PS_{dif,proximal cells to vessels}, intrinsic clearance by passive diffusion from proximal cells to vessels; PS_P‐gp, efflux intrinsic clearance by P‐gp; PS_tissue,in, intrinsic clearance by passive diffusion from extracellular to intracellular space of each tissue; PS_tissue,out, intrinsic clearance by passive diffusion from intracellular to extracellular space of each tissue; PS_tissue,ratio, PS_tissue,in/PS_tissue,out; R _B, blood‐to‐plasma concentration ratio; R _dif,eff, PS_dif,eff/PS_P‐gp on apical membrane; R _dif,inf, PS_dif,inf/PS_act,inf on sinusoidal or basolateral membrane; SF_Kp, common scaling factor to in silico K _p values in each tissue; R_{dif,inf,kidney}, _Rdif,inf in the kidney; SF_{renal permeability}, common scaling factor to intrinsic clearance by passive diffusion in kidney; T _lag, lag time in intestinal absorption; UGT, uridine diphosphate‐glucuronosyl transferase.

^a Initial value for optimization.

^b Calculated as f _B = f _Plasma/R _B with the previous reports. ³⁷ , ,47

^c Calculated based on in silico methodology.

^d Calculated based on the previous report. ¹⁵

^e Assumption.

^f Extracted value from the Simcyp software package version 20.1.

^g Adjusted manually to be comparable to the previous model. ¹⁵

^h Adjusted manually to reproduce observed F _a F _g.

ⁱ Details are provided in the Method section.

^j Assumed to be equal to γ _{eff,enterocytes}.

^k Adjusted manually to reproduce observed CL_renal.

^l Calculated by multiplying the apparent permeability coefficient obtained from Caco‐2 cells by the surface area of each segment. ²² , ^,40

^m Assumed to be equal to PS_{dif,distal cells to tubule}.

ⁿ Assumed to be equal to PS_{dif,collecting duct cells to tubule}.

^o γ_inf and γ_eff of talinolol and quinidine in proximal cells, distal cells, and collecting duct cells were calculated according to the previous report. ¹⁷