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 (Papp) 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.CompoundMolecular weight (g/mol)Ionization classification at pH 7.4Papp (A to B)Main elimination pathwaysECCS
1Midazolam325.78Base135CYP3A4FDA, 20202
2Quinidine324.42Base280CYP3A4FDA, 20202
3Dextromethorphan271.40Base291CYP2D6FDA, 20202
4Diclofenac296.15Acid132.8Lee et al., 2017CYP2C9FDA, 20201a
5Tolbutamide270.35Acid173CYP2C9FDA, 20201a
6Bupropion239.74Base388CYP2B6FDA, 20202
7Propranolol259.34Base287CYP2D6/multipleMcGinnity et al., 20042
8Verapamil454.60Base197CYP3A4McGinnity et al., 20042
9Clozapine326.82Base199CYP1A2/multipleMcGinnity et al., 20042
10Efavirenz315.68Acid158CYP2B6/2A6 > 3A4 and 1A2Simcyp2
13Ethinylestradiol296.40Neutral233CYP1A2/2C9/3A4, UGT1A1 and SULTsSimcyp2
14Mycophenolic acid320.34Acid50UGT1A9/2B7Minor/(MRP2)Picard et al., 2005; Patel et al., 20171a
15Clopidogrel321.82Base257CES1/CYP2C19Polasek et al., 20112
16Oseltamivir312.40Base45CES1FDA review3a
17Irinotecan586.68Base21CES1/2/CYP3AP-gp/MRP2Mathijssen et al., 2001; Toshimoto et al., 20174
18SN-38392.40Base37UGT1A1P-gp/MRP2/BCRPMathijssen et al., 2001; Toshimoto et al., 20174
19Benzydamine309.41Base302FMO(1/)3 (and UGT)Baldock et al., 1990; Bohnert et al., 20162
20Cyclosporine A1202.60Neutral68CYP3A4(P-gp)Simcyp; (Thiel et al., 2015)2
21Ketoconazole531.43Base171CYP3A4 (+UGT/FMO/deacetylation)Kim et al., 20172
22Atorvastatin558.64Acid11CYP3A4OATP1B1Maeda et al., 20113b
23Fluvastatin411.47Acid26Li et al., 2011CYP2C9(OATP1B1/)BCRPFujino et al., 2004; Keskitalo et al., 2009; Kunze et al., 20143b
24Simvastatin418.57Neutral52CYP3A4(OATP1B1/1B3)Simcyp; (Kunze et al., 2014)2
25Pravastatin424.53Acid3.22MinorOATP1B1/MRP2Thiel et al., 20153b
26Rosuvastatin481.54Acid0 (BLOQ)MinorOATP1B1/NTCP/BCRPSimcyp3b
27Famotidine337.45Base12Minor (S-oxide formation)OCT2 (renal)Echizen and Ishizaki, 1991; FDA, 20204
29Fexofenadine501.68Zwitterions0 (BLOQ)OATP1B3 and unknown mechanismShimizu et al., 20053b
30Memantine179.30Base320OCT2 (renal)FDA, 20202
31Repaglinide452.59Zwitterions41CYP3A4/2C8OATP1B1Drug label3b
32Furosemide330.75Acid36Biliary excretionOAT3 (renal)FDA, 20203a
33Valsartan435.52Acid0 (BLOQ)P450 (minor)OATP1B1/1B3/MRP2Waldmeier et al., 1997; FDA, 20203b
34Cimetidine252.34Base35P450 (minor)OAT3/OCT2 (renal)Somogyi and Gugler, 1983; McGinnity et al., 2004; FDA, 20204
35Digoxin780.94Neutral54Zhang and Morris, 2003MinorP-gp(Caldwell and Cline, 1976); Simcyp2
36Talinolol363.50Base29Anderle et al., 1998(CYP3A4)P-gp (and MRP2)Giessmann et al., 2004; FDA, 20204
  • BLOQ, below limit of quantification; NTCP, Na+-taurocholate cotransporting polypeptide.