Enzymes and transporters involved in the NDA/BLA elimination pathways
| Drug Name | Main Elimination Route | Enzymes Involveda | Transporters Involveda | Reference |
|---|---|---|---|---|
| Ado-trastuzumab emtansine (T-DM1) | DM1: metabolism; no mass balance study for T-DM1 | T: Proteolytic enzymesb; DM1: CYP3A4b, CYP3A5b | P-gpc | (FDA, 2013l) |
| Afatinib | Minimal metabolism, fecal (85% mostly as parent) | Flavin monoooxygenaseb, cytochrome P450s | P-gp, BCRPd | (FDA, 2013i) |
| Alogliptin | Minimal metabolism, renal (76% mainly as parent), fecal (13%) | CYP2D6, CYP3A4 | Nonec | (FDA, 2013q) |
| Canagliflozin | Metabolism, fecal (60.4% mainly as parent), renal (32.5 mainly as metabolites) | UGT2B4b, UGT1A9b, CYP3A4, CYP2D6 | P-gp, MRP2 | (FDA, 2013k) |
| Conjugated estrogens and bazedoxifene | E: metabolism, renal (as parents and metabolites); B: metabolism, fecal (85% mainly as parent) | E: CYP3A4b; B: UGT1A1b, UGT1A10b, UGT1A8 | Not testede | (FDA, 2013g) |
| Dabrafenib | Metabolism, fecal (71%), renal (23%) | CYP2C8b, CYP3A4b, CYP2C9, CYP2C19 | P-gpc | (FDA, 2013w) |
| Dimethyl fumarate | Metabolism, exhalation of CO2 (60%), renal (15.5%) | Esterasesb, tricarboxylic acid cycleb (non–cytochrome P450) | Nonec | (FDA, 2013x) |
| Dolutegravir | Metabolism, fecal (53% as parent), renal (31% mainly as metabolites) | UGT1A1, UGT1A3, UGT1A9 | P-gp, BCRPd | (FDA, 2013y) |
| Eslicarbazepine acetate | Metabolism, renal (90% as parent and metabolites) | Non–cytochrome P450 hydrolytic enzymesb, UGT1A9, UGT2B4, UGT2B17 | Not tested | (FDA, 2013c) |
| Fluemetamol F-18 | Fecal (52%), renal (37%) | Not available | Not tested | (FDA, 2013z) |
| Fluticasone and vilanterol | F: metabolism, fecal (90%); V: metabolism, renal (70%), fecal (30%) | F: CYP3A4b; V:CYP3A4b | F: P-gpb; V: P-gpb,c | (FDA, 2013d) |
| Gadoterate meglumine | Renal (86.6% as parent) | None | Not tested | (FDA, 2013f) |
| Ibrutinib | Metabolism, fecal (80.6% mostly as metabolites) | CYP3A4b, CYP2D6 | Nonec | (FDA, 2013j) |
| Luliconazole | Metabolism (topical use) | CYP2D6b, CYP3A4b | Not tested | (FDA, 2013n) |
| Macitentan | Metabolism, renal (50% as inactive metabolites), fecal (24%) | CYP3A4 (99%)b, CYP2C19 | None | (FDA, 2013s) |
| Mipomersen | Metabolism in tissues, renal (< 2%) | Endonucleases and exonucleasesb (non–cytochrome P450) | Nonec | (FDA, 2013m) |
| Obinutuzumab | Minimal hepatic or renal elimination | Proteolytic enzymesb | Not tested | (FDA, 2013h) |
| Ospemifene | Metabolism, fecal (75% mainly as metabolites) | CYP3A4 (40-55%)b, CYP2C9 (25%)b, CYP2C19 (25%)b | Nonec | (FDA, 2013t) |
| Pomalidomide | Metabolism, renal (73% mainly as metabolites), fecal (15% mainly as metabolites) | CYP1A2 (54%)b, CYP3A4 (30%)b, CYP2C19, CYP2D6, non–cytochrome P450 hydrolytic enzymes | P-gpc | (FDA, 2013u) |
| Radium Ra 223 dichloride | Fecal | None | Not tested | (FDA, 2013aa) |
| Riociguat | Metabolism, fecal (53% mainly as metabolites), renal (40% mainly as metabolites) | CYP1A1b, CYP3A, CYP2C8, CYP2J2 | P-gp, BCRPd | (FDA, 2013a) |
| Simeprevir | Metabolism, fecal (91% mainly in metabolites) | CYP3A4b, CYP2C8, CYP2C19 | OATP1B1, OATP1B3, P-gp, MRP2, OATP2B1, mBcrpf | (FDA, 2013r) |
| Sofosbuvir | Metabolism, renal (80% mainly as metabolites), fecal (14% mainly as parent) | Non–cytochrome P450 hydrolytic enzymesb (Cathepsin A, carboxylesterase 1, etc.) | P-gp, BCRP | (FDA, 2013v) |
| Technetium Tc-99M tilmanocept | Not available | None | Not tested | (FDA, 2013o) |
| Trametinib | Minimal metabolism, fecal (50-75% as parent), renal (<20%) | CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4, non–cytochrome P450 hydrolytic enzymes | Noned | (FDA, 2013p) |
| Umeclidinium and vilanterol | U: metabolism, fecal (92% as parent and metabolites); V: metabolism, renal (70% as metabolites), fecal (30% as metabolites) | U: CYP2D6b, CYP3A4, UGTs; V: CYP3A4b, CYP2D6 | U: P-gp, OCT1, OCT2, V: P-gp | (FDA, 2013b) |
| Vortioxetine | Metabolism, fecal (59% as metabolites), renal (26% as metabolites) | CYP2D6b, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, CYP2B6, UGTs | Nonec | (FDA, 2013e) |
↵a Determined in vitro.
↵b Enzymes described as major contributors in the NDA reviews are underlined.
↵c Only P-gp tested.
↵d Only P-gp and BCRP tested.
↵e Previously published study showed bazedoxifene is a substrate of P-gp.
↵f Murine Bcrp was tested as a stable cell-line expressing human BCRP was not available.