. 2020 Dec 15;10(1):5–17. doi: 10.1002/psp4.12571

Table 1.

Summary of the physiologically‐based pharmacokinetic input parameters for M‐I to M‐V

Rosuvastatin model parameters
		MW fu Blood‐to‐plasma ratio Log of the octanol:water partition coefficient Compound type pKa Main plasma binding protein		481.54 0.107 0.625 2.4 Monoprotic acid 4.27 Human serum albumin
	M‐I ¹⁷	M‐II ²²	M‐III ²³	M‐IV ²⁴	M‐V ²⁵
Absorption
P _app	Caco‐2 with inhibitors (passive)	Caco‐2 with inhibitors (passive)	Caco‐2 no inhibitors (passive)	Caco‐2 no inhibitors (passive + active)	MDCK II (passive)
Reference P _app (10⁻⁶ cm/second)	Propranolol (measured)	Propranolol (measured)	Propranolol (from library file)	Propranolol (from library file)	Four reference compounds (measured)
P _eff (10⁻⁴ cm/second)	0.855	0.855	0.036	0.184	0.161
Distribution
V _ss method	Method 2 K _p = 1	Method 2 K _p = 1	Method 2 K _p = 1	Method 2 + rat distribution data K _p = 1	Method 2 K _p = 4.85
V _ss (L/kg)	0.117	0.117	0.117	0.70	0.385
Metabolism
HLM	HLM CL_int	HLM CL_int	HLM CL_int	CYP3A4 CL_int UGT1A1 V _max/K _m UGT1A3 V _max/K _m	HLM CL_int
Intestinal transport
Uptake	—	—	Apical uptake CL_int,T a	—	OATP2B1 CL_int,T b
Efflux	BCRP CL_int,T b	BCRP CL_int,T b	BCRP J_max a/K _m c	—	BCRP J_max b/K _m c
Hepatic transport
Uptake	OATP1B1 CL_int,T ^d OATP1B3 CL_int,T ^d NTCP CL_int,T ^d	OATP1B1 CL_int,T ^d OATP1B3 CL_int,T ^d NTCP CL_int,T ^d	OATP1B1 CL_int,T ^d OATP1B3 CL_int,T ^d NTCP CL_int,T ^d	OATP1B1 J _max/K _m (and REF) ^c OATP1B3 J _max/K _m (and REF) ^c NTCP CL_int,T (and REF) ^c OATP2B1 J _max/K _m (and REF) ^c	OATP1B1 CL_int,T ^d OATP1B3 CL_int,T ^d NTCP CL_int,T ^d OATP2B1 CL_int,T ^d
Efflux	BCRP CL_int,T c	BCRP CL_int,T c	BCRP CL_int,T ^c MRP4 CL_int,T ^b	Canalicular efflux CL_int,T (and REF) ^c MRP4 J _max/K _m (and REF) ^c	BCRP CL_int,T ^c MRP4 CL_int,T ^c
CL_PD (mL/minute/10⁶ cells)	SCHH (one study)	SCHH (one study)	SCHH (one study)	SCHH (one study)	SCHH (meta‐analysis)
Renal elimination
CL_R (L/hour)	In vivo value	—	—	—	In vivo value
Uptake transport	—	OAT3 CL_int,T b	OAT3 CL_int,T a	OAT3 J _max/K _m c	—
Efflux transport	—	BCRP CL_int,T b	BCRP CL_int,T a	MRP4 J _max/K _m c	—
CL_PD (mL/minute/10⁶ cells)	—	Included	Not included	Included	—

BCRP, breast cancer resistance protein; Caco‐2, human colon cancer cell line; CL_int, intrinsic clearance; CL_PD, passive diffusion clearance; CL_R, renal clearance; fu, fraction unbound; HLM, human liver microsomes; J _max, maximum rate of transport; K _m, Michaelis‐Menten constant; K _p, tissue‐to‐plasma partition coefficient; MDCK II, Madin‐Darby canine kidney cell line II; MW, molecular weight; MRP, multidrug resistance protein; NTCP, sodiuM‐taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; P _app, apparent permeability; P _eff, effective permeability; REF, relative expression factor; SCHH, sandwich culture human hepatocytes; Vmax, maximum velocity of the metabolic reaction; V _ss, steady‐state volume of distribution.

^{^a}

“Model fit.”

^{^b}

Sensitivity analysis.

^{^c}

In vitro data.

^{^d}

Global CL_int,T fit using clinical data, fraction transported determined from in vitro data.