TABLE 3.

Summary of inhibitory properties and pharmacokinetic parameters of clopidogrel (CP), clopidogrel carboxylic acid (CPC), clopidogrel acyl-β-D-glucuronide, 2-oxo clopidogrel at clinically relevant doses.

Perpetrator	MW	fu	IC50 OTAP1B1	IC50 OTAP1B3	IC50 BCRP	Dose	I1	I2	Imax,u	Iin,max,u	DDI potential for intestinal efflux transporter	DDI potential for hepatic uptake transporter	DDI potential for canalicular efflux transporter
			μM		μM	mg	μM	μM	μM	μM	Cut-off:10; 0.1	Cut-off: 0.1	Cut-off: 0.1
Clopidogrel	321.822	0.02 Tornio et al. (2014)	3.95(CER) Tamraz et al. (2013)1.8 (e17βG) Elsby et al. (2016)27.39※	>50※	63 Elsby et al. (2016)104.3 Varma et al. (2019)≈0.001※	75	0.0010 Itkonen et al. (2015)	932.19	0.00002	0.31	I2/IC50 BCRP >> 10	Iin,max,u/IC50 OATP1B1 = 0.011	Imax,u/IC50 BCRP≈0.02
						300	0.0089 Itkonen et al. (2015)	3,728.77	0.00018	1.24	I2/IC50 BCRP >> 10	Iin,max,u/IC50 OATP1B1 = 0.045	Imax,u/IC50 BCRP ≈ 0.18
Clopidogrel carboxylic acid derivative	307.795	0.06 Tornio et al. (2014)	>100 (CER; ES) Tamraz et al. (2013) > 50※	>50※	5.96※	75	7.38 Itkonen et al. (2015)	N/A	0.443	N/A	Imax,u/IC50 BCRP = 0.074	Imax,u/IC50 OATP1B1 < 0.1	Imax,u/IC50 BCRP = 0.074
						300	31.90 Itkonen et al. (2015)	N/A	1.914	N/A	Imax,u/IC50 BCRP = 0.321	Imax,u/IC50 OATP1B1 < 0.1	Imax,u/IC50 BCRP = 0.321
Clopidogrel acyl glucuronide	483.919	0.1 Tornio et al. (2014)	10.9 (CER) Tamraz et al. (2013)33.5 (ES) Tamraz et al. (2013)	N/A	N/A	75	1.72 Itkonen et al. (2015)	N/A	0.172	N/A	N/A	Imax,u/IC50 OATP1B1 = 0.016	N/A
						300	4.77 Itkonen et al. (2015)	N/A	0.477	N/A	N/A	Imax,u/IC50 OATP1B1 = 0.044	N/A
2-Oxo clopidogrel	337.821	0.02 Tornio et al. (2014)	8.18(CER) Tamraz et al. (2013)8.97 (ES) Tamraz et al. (2013)	N/A	N/A	75	0.004	N/A	0.00008	N/A	N/A	Imax,u/IC50 OATP1B1 << 0.1	N/A
						300	0.016 Kim et al. (2016)	N/A	0.0003	N/A	N/A	Imax,u/IC50 OATP1B1 << 0.1	N/A

MW, molecular weight; f_u, fraction unbound in human plasma; I₁, peak plasma concentrations at steady state of CP, CPC, clopidogrel acyl-β-D-glucuronide, and 2-oxo clopidogrel were obtained from two clinical trials (Itkonen et al., 2015; Kim et al., 2016) except that I₁ of 2-oxo clopidogrel at a maintenance dose of 75 mg CP was calculated from the I₁ value at a loading dose of 300 mg CP assuming linear pharmacokinetics; I₂, maximal theoretical gastrointestinal concentration (calculated from dose [mol]/250 ml); I_max,u, unbound steady-state plasma peak concentration, calculated as fu×I₁; I_in,max,u, steady-state unbound liver inlet concentration, calculated as fu× [I₁ + (F_a×k_a×Dose/Q_h)], where F_a is the fraction absorbed (taken to be 1.0 as the default value), k_a is the absorption rate constant (as default taken to be 0.1 min⁻¹), Q_h is hepatic blood flow (1,500 ml/min) (U.S. Department, 2020); IC₅₀, half maximal inhibitory concentration; ^※IC₅₀ value obtained from this study using rosuvastatin (RSV) as a substrate; e17βG, estradiol 17β-glucuronide; CER, cerivastatin; ES, estrone sulfate; and NA, not applicable. Whenever IC₅₀ values obtained with RSV as a substrate were unavailable, the smallest value among all reported IC₅₀ values obtained with other substrates (e.g., CER) was selected for the worst case estimate. The DDI potentials of different transporters were calculated according to the recommended equations (U.S. Department, 2020; Parkinson, 2019). For the intestinal efflux transporter, DDI potential of the orally administered drug was I₂/IC₅₀, and the cut-off value was 10; for the metabolite of the orally administrated drug, the DDI potential was I_max,u/IC₅₀, and the cut-off value was 0.1; for the hepatic uptake and biliary efflux transporters, DDI potential of both parent forms or the metabolite was I_in,max,u/IC₅₀, and the cut-off value was 0.1. All IC₅₀ values used for the calculation of DDI potentials were from this study except the IC_50OTAP1B1 value of clopidogrel acyl-β-D-glucuronide and 2-oxo clopidogrel, and the DDI potential for OATP1B3 was not calculated because the inhibitory effect was not obtained in this study or from previous reports.