TABLE 1

Data supporting ECCS classification of 36 marketed drugs and collected data on main elimination pathways

Table 1 summarizes physicochemical parameters used for the ECCS classification of 36 marketed drugs. The pathways (enzymes and transporters) involved in hepatic (and renal) elimination are provided. Pathway descriptions are provided in parentheses if the clinical relevance of the elimination pathways is not confirmed. Passive permeability (P_app) in the apical to basal direction in LLC-PK1 cells was measured in the present study or was taken from the literature (Caco-2 permeability) in the instances for which the reference is provided. Documentation for physiologically based pharmacokinetic models for the marketed drugs are provided with the SimCYP software platform and have been verified to show good performance for prediction of PK profiles and drug-drug interaction potential. Therefore, the model input parameters and drug disposition pathways were used for the current assessment.

No.	Compound	Molecular weight (g/mol)	Ionization classification at pH 7.4	P_app (A to B)		Main elimination pathways			ECCS
No.	Compound	Molecular weight (g/mol)	Ionization classification at pH 7.4	(nm/s)	Reference	Enzyme	Transporter	Reference	ECCS
1	Midazolam	325.78	Base	135		CYP3A4	—	FDA, 2020	2
2	Quinidine	324.42	Base	280		CYP3A4	—	FDA, 2020	2
3	Dextromethorphan	271.40	Base	291		CYP2D6	—	FDA, 2020	2
4	Diclofenac	296.15	Acid	132.8	Lee et al., 2017	CYP2C9	—	FDA, 2020	1a
5	Tolbutamide	270.35	Acid	173		CYP2C9	—	FDA, 2020	1a
6	Bupropion	239.74	Base	388		CYP2B6	—	FDA, 2020	2
7	Propranolol	259.34	Base	287		CYP2D6/multiple	—	McGinnity et al., 2004	2
8	Verapamil	454.60	Base	197		CYP3A4	—	McGinnity et al., 2004	2
9	Clozapine	326.82	Base	199		CYP1A2/multiple	—	McGinnity et al., 2004	2
10	Efavirenz	315.68	Acid	158		CYP2B6/2A6 > 3A4 and 1A2	—	Simcyp	2
11	Rosiglitazone	357.43	Acid	152		CYP2C8/3A4	—	Simcyp	1a
12	Omeprazole	345.42	Neutral	253		CYP2C19/3A4	—	Simcyp	2
13	Ethinylestradiol	296.40	Neutral	233		CYP1A2/2C9/3A4, UGT1A1 and SULTs	—	Simcyp	2
14	Mycophenolic acid	320.34	Acid	50		UGT1A9/2B7	Minor/(MRP2)	Picard et al., 2005; Patel et al., 2017	1a
15	Clopidogrel	321.82	Base	257		CES1/CYP2C19	—	Polasek et al., 2011	2
16	Oseltamivir	312.40	Base	45		CES1	—	FDA review	3a
17	Irinotecan	586.68	Base	21		CES1/2/CYP3A	P-gp/MRP2	Mathijssen et al., 2001; Toshimoto et al., 2017	4
18	SN-38	392.40	Base	37		UGT1A1	P-gp/MRP2/BCRP	Mathijssen et al., 2001; Toshimoto et al., 2017	4
19	Benzydamine	309.41	Base	302		FMO(1/)3 (and UGT)	—	Baldock et al., 1990; Bohnert et al., 2016	2
20	Cyclosporine A	1202.60	Neutral	68		CYP3A4	(P-gp)	Simcyp; (Thiel et al., 2015)	2
21	Ketoconazole	531.43	Base	171		CYP3A4 (+UGT/FMO/deacetylation)	—	Kim et al., 2017	2
22	Atorvastatin	558.64	Acid	11		CYP3A4	OATP1B1	Maeda et al., 2011	3b
23	Fluvastatin	411.47	Acid	26	Li et al., 2011	CYP2C9	(OATP1B1/)BCRP	Fujino et al., 2004; Keskitalo et al., 2009; Kunze et al., 2014	3b
24	Simvastatin	418.57	Neutral	52		CYP3A4	(OATP1B1/1B3)	Simcyp; (Kunze et al., 2014)	2
25	Pravastatin	424.53	Acid	3.22		Minor	OATP1B1/MRP2	Thiel et al., 2015	3b
26	Rosuvastatin	481.54	Acid	0 (BLOQ)		Minor	OATP1B1/NTCP/BCRP	Simcyp	3b
27	Famotidine	337.45	Base	12		Minor (S-oxide formation)	OCT2 (renal)	Echizen and Ishizaki, 1991; FDA, 2020	4
28	Gemfibrozil	250.33	Acid	82		UGT2B7	—	Simcyp	1a
29	Fexofenadine	501.68	Zwitterions	0 (BLOQ)		—	OATP1B3 and unknown mechanism	Shimizu et al., 2005	3b
30	Memantine	179.30	Base	320		—	OCT2 (renal)	FDA, 2020	2
31	Repaglinide	452.59	Zwitterions	41		CYP3A4/2C8	OATP1B1	Drug label	3b
32	Furosemide	330.75	Acid	36		Biliary excretion	OAT3 (renal)	FDA, 2020	3a
33	Valsartan	435.52	Acid	0 (BLOQ)		P450 (minor)	OATP1B1/1B3/MRP2	Waldmeier et al., 1997; FDA, 2020	3b
34	Cimetidine	252.34	Base	35		P450 (minor)	OAT3/OCT2 (renal)	Somogyi and Gugler, 1983; McGinnity et al., 2004; FDA, 2020	4
35	Digoxin	780.94	Neutral	54	Zhang and Morris, 2003	Minor	P-gp	(Caldwell and Cline, 1976); Simcyp	2
35	Digoxin	780.94	Neutral	35–45		Minor	P-gp	(Caldwell and Cline, 1976); Simcyp	4
36	Talinolol	363.50	Base	29	Anderle et al., 1998	(CYP3A4)	P-gp (and MRP2)	Giessmann et al., 2004; FDA, 2020	4

BLOQ, below limit of quantification; NTCP, Na⁺-taurocholate cotransporting polypeptide.