TABLE 3

Inhibitory properties and pharmacokinetic parameters of drugs coadministered with rosuvastatin in a clinical interaction study

Perpetrator Drug	Dose	MW	[I₂]	BCRP K_i	[I₂]/K_i Ratio	[I_{gut max}]	C_{max total}	f_u	[I_{inlet max u}]	OATP1B1 K_i	Biliary BCRP
Perpetrator Drug	Dose	MW	[I₂]	BCRP K_i	[I₂]/K_i Ratio	[I_{gut max}]	C_{max total}	f_u	[I_{inlet max u}]	OATP1B1 K_i	I_{inlet max u} / K_i Ratio
	mg		μM	μM		μM	μM		μM	μM
Fostamatinib	100	578.52	691	0.05	13,820
R406				0.031		58	1.9	0.018	0.289	>10	9.3
Eltrombopag	75	442.5	678	2.1	323	29^{^a}	17.7	0.01	0.236	2.7^{^b}	0.11
Darunavir	600	547.73	4382	75	58	73^{^c}	10.6^{^d}	0.05	1.261	4.3	0.02
Lopinavir	400	628.8	2545	8.7	293	42^{^e}	14.6	0.02	0.462	0.43	0.05
Clopidogrel	75	321.9	932	63	15	78	0.0099	0.02^{^f}	0.311	1.8	0.005
Clopidogrel	300	321.9	3728	63	59	311	0.130	0.02^{^f}	1.245	1.8	0.02
Ezetimibe	10	409.4	98	2.9	34	2.4^{^g}	0.014	0.10	0.050	2.2	0.02
Fenofibrate/fenofibric acid	67	360.83	743	170	4.4	62	25.8	0.01	0.398	20^{^h}	NA
Fluconazole	200	306.3	2612	No inhibition	NA	218	34.6^{^f}	0.89	69.536	No inhibition	NA

C_{max total}, mean steady-state maximum plasma concentration for total (bound plus unbound) drug measured in the clinical interaction study with rosuvastatin; f_u, fraction unbound [taken from the drug label accessed via the Pharmapendium database (http://www.pharmapendium.com)]; I₂, maximal theoretical gastrointestinal concentration (calculated from dose [mol]/250 ml); I_{gut max}, maximum enterocyte concentration, calculated as (F_a × k_a × dose/Q_ent), where F_a is the fraction absorbed (as default taken to be 1.0), k_a is the absorption rate constant (as default taken to be 0.1 min⁻¹), and Q_ent is the enterocyte blood flow (300 ml/min ≡ 18 l/h; Agarwal et al., 2013); I_{inlet max u}, maximum unbound liver inlet concentration, calculated as f_u × [(C_{max total}) + (F_a × k_a × dose/Q_h)], where F_a is the fraction absorbed (as default taken to be 1.0), k_a is the absorption rate constant (as default taken to be 0.1 min⁻¹), and Q_h is hepatic blood flow (1500 ml/min); K_i, absolute inhibition constant (assuming competitive inhibition; equates to IC₅₀ in these assays as probe substrate concentration used is < <<< K_m); MW, molecular weight [taken from the drug label accessed via Pharmapendium database (http://www.pharmapendium.com)]; NA, not applicable.
↵^a Value for F_a taken to be 0.52 (drug label).
↵^b Value taken from Allred et al. (2011).
↵^c Value for k_a taken to be 0.02 (Arab-Alameddine et al., 2014).
↵^d Value taken from Kakuda et al. (2011).
↵^e Value for k_a taken to be 0.02 (Duangchaemkarn and Lohitnavy, 2013).
↵^f Value taken from drug pharmacokinetic profile on the University of Washington Drug Interaction Database (http://www.druginteractioninfo.org).
↵^g Value for k_a taken to be 0.03 (Ezzet et al., 2001).
↵^h Value for fenofibric acid taken from Yamazaki et al. (2005).