TABLE 4

Assigned and estimated parameters used for simulation of E₂17G and E₂3S17G profiles/parameters in the recirculating perfused Wistar and TR⁻ rat liver preparations according to the liver PBPK model

Parameters	TR⁻ Livers	Wistar Livers
V_R, volume of reservoir (ml)	180^{^a}	182^{^a}
V_LB, volume of sinusoid (ml)	1.82^{^b}	1.81^{^b}
V_L, volume of liver tissue (ml)	9.11^{^b}	9.07^{^b}
V_bile, volume of canaliculi and bile cannula (ml)	0.108^{^c}	0.108^{^c}
Q_bile, bile flow rate (μl/min)	2.4^{^d}	6.3^{^d}
f_B, f_L, f_B{mi}, f_L{mi}, unbound fractions for E₂17G in blood and liver, E₂3S17G in perfusate and liver, respectively	0.23^{^d}	0.22^{^d}
CL_in,, influx clearance for E₂17G (ml/min)	546^{^e}	546^{^e}
CL_ef, efflux clearance for E₂17G (ml/min)	5.75^{^f}	1.35^{^g}
CL_in{mi}, influx clearance for E₂3S17G (ml/min)	546^{^h}	546^{^h}
CL_ef{mi}, efflux clearance for E₂3S17G (ml/min)	10.9^ⁱ	2.56^{^g}
CL_int,met^D→Mi), sulfation intrinsic clearance (ml/min)	22.4^{^j}	22.4^{^k}
CL_int,met^Mi→D), desulfation intrinsic clearance (ml/min)	31.1^{^l}	4.81^{^k}
CL_int,sec, secretory intrinsic clearance for E₂17G (ml/min)	0.02^{^m}	1.90^{^k}
CL_int,sec{mi}, E₂3S17G secretory intrinsic clearance (ml/min)	0.008^{^m}	2.54^{^k}
ef_m″, effective coefficient for metabolite formation	0.00026	0.346
ef_m′, effective recycling coefficient	0.00089	0.078

↵a Averaged value from t = 0 (200 ml) to time = 2 h.
↵b From multiple indicator dilution studies (Pang et al., 1988).
↵c Sum of bile volume of canaliculi (0.004 ml/g liver) and bile cannula volume (20 cm of polypropylene tubing with i.d. of 0.58 mm).
↵d Observations for unbound fractions: f_B is the determined value (Sun et al., 2006) and f_L, f_B{mi}, and f_L{mi} were set to equal f_B for simplicity.
↵e Assigned, same as Wag/Rij rat liver from Sun et al. (2006), and according to protein expression of Oatps (Fig. 2).
↵f According to eq. 1.
↵g According to ratio of relative Mrp3 protein expression in Fig. 2 (TR⁻/Wistar = 4.2).
↵h Based on the assumption that CL_in{mi} = CL_in.
↵i According to eq. 2.
↵j Based on similar protein expressions of Sults for TR⁻ and Wistar rat livers in Fig. 2.
↵k Estimate for Wistar rat derived from preliminary data fitting, with fixed basolateral influx and efflux parameters.
↵l According to eq. 3.
↵m Optimized by trial and error.