Enzymes and transporters involved in the NDA elimination pathways
| Compound Name | Main Elimination Route | Enzyme Involved | Transporter Involved | Reference |
|---|---|---|---|---|
| Edoxaban | Minimal metabolism, 62% in the urine and 35% in the feces renal (primarily as parent in both) | Carboxyesterase 1, phase II conjugation, CYP3A | P-gp, OATP1B1 | FDA (2015w) |
| Palbociclib | Metabolism, 74.1% in the feces and 17.5% in the urine (percentage of parent versus metabolites not available) | CYP3A,a SULT2A1 | P-gp, BCRP | FDA (2015n) |
| Lenvatinib | Metabolism, 64% in the feces and 25% in the urine (parent <2.5% overall in both) | Aldehyde oxidase, CYP3A4, other P450s (not specified), phase II enzymes like GSH conjugation and other biotransformation | P-gp, BCRP | FDA (2015q) |
| Panobinostat | Metabolism, 29%–51% in the urine (parent <2.5%) and 44%–77% in the feces (parent <3.5%), | CYP3A,a CYP2D6, 2C19, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT2B4 | P-gp | FDA (2015l) |
| Ceftazidime (and avibactam) | Not metabolized in the liver, renal excretion, 97% in the urine (80%–90% as parent) | None | OAT1, OAT3 | FDA (2015d) |
| Isavuconazonium sulfate | Metabolism, 46% in the feces and 46% in the urine (active isavaconazole <1%) | Esterases,a CYP3A4,a CYP3A5,a UGTs | None | FDA (2015i) |
| Cholic acid | Joins the endogenous bile acid pool in the enterohepatic circulation mainly in conjugated forms; any cholic acid not absorbed will be excreted in the feces alone or as deoxycholic acid | CYP3A4, UGT2A1 and UGT2A2b | BSEP, BCRPb | Deo and Bandiera (2008); Blazquez et al. (2012); Perreault et al. (2013); FDA (2015f) |
| Ivabradine | Metabolism, metabolites 37% in the urine and 47% in the feces (4% as parent in each) | CYP3A4a | P-gp | FDA (2015g) |
| Deoxycholic acid | Not metabolized, excreted in the feces as parent | None | BSEP | FDA (2015p) |
| Eluxadoline | Not metabolized, 82% in the feces and 0.12% in the urine (percentage of parent versus metabolites not assessed) | Nonec | OAT3, OATP1B1, BSEP, MRP2 | FDA (2015zc) |
| Cangrelor | Metabolism in plasma, 58% in the urine and 35% in the feces | Nucleotidasesa | N/T | FDA (2015o) |
| Lumacaftor (and ivacaftor) | Not extensively metabolized, biliary excretion, 51% in the feces as parent | Mainly via oxidation and glucuronidation enzymes | N/T | FDA (2015u) |
| Sacubitril (and valsartan) | Metabolism, 51.7%–67.8% in the urine and 36.9%–48.3% in the feces (mainly as active metabolite LBQ657) | Esterasesa | P-gp; LBQ657: OATP1B1/3, OAT3 | FDA (2015k) |
| Brexpiprazole | Metabolism, 46% in the feces (14% as parent) and 25% in the urine (parent <1%) | CYP3A4,a CYP2D6a | P-gp, BCRP | FDA (2015v) |
| Sonidegib | Metabolism, 70% in the feces and 30% in the urine | CYP3Aa | None | FDA (2015t) |
| Daclatasvir | Metabolism, biliary excretion, 88% in the feces (53% as parent), 6.6% in the urine (primarily as parent) | CYP3A,a CYP2C8 | P-gp | FDA (2015j) |
| Flibanserin | Metabolism, 51% in the feces and 44% in the urine | CYP3A4,a CYP2C19a | Noned | FDA (2015a) |
| Rolapitant | Metabolism, biliary excretion, 73% in the feces (mainly as parent)and 14% in the urine (primarily as metabolites) | CYP3A4a | None | FDA (2015za) |
| Uridine triacetate | Metabolism and catabolism, renal excretion | Esterasesa | P-gp, nucleoside transporters | FDA (2015ze) |
| Cariprazine | Metabolism, 40.1% in the feces and 20.8% in the urine (parent and active metabolites accounts for 6%–8% overall in both) | CYP3A4,a CYP2D6, glucuronidation and sulfation enzymes | None | FDA (2015zf) |
| Trifluridine (and tipiracil) | Not metabolized, mainly renal excretion as parent, no mass balance study | None | N/T | FDA (2015r) |
| Insulin delgudec | Proteolytic degradation | N/T, mostly by proteolytic enzymes | N/T | FDA (2015y) |
| Aripiprazole lauroxil | Hepatic metabolism | Parent: esterase-a and water-mediated hydrolysis,a aripiprazole: CYP3A4a and CYP2D6a | N/T | FDA (2015c) |
| Patiromer | Not absorbed or metabolized, entirely excreted in the feces | N/T (not likely to be metabolized) | N/T | FDA (2015zb) |
| Trabectedin | Metabolism, 58% in the feces and 6% in the urine (negligible as parent in each) | CYP3A4,a other P450s (not specified) | P-gp | FDA (2015zf) |
| Elvitegravir, cobicistat, emtricitabine (and tenofovir alafenamide fumarate) | Metabolism, renal excretion (mainly as active metabolite tenofovir) | Cathepsin A,a carboxyesterase 1, CYP3A4 (minimal) | P-gp, BCRP, OATP1B1/3 | FDA (2015m) |
| Cobimetinib | Metabolism, 76% in the feces (6.6% as parent) and 18% in the urine (1.6% as parent) | CYP3A, UGT2B7 | P-gp | FDA (2015h) |
| Osimertinib | Metabolism, 68% in the feces and 14% in urine (2% as parent overall in both) | CYP3Aa | P-gp, BCRP | FDA (2015x) |
| Ixazomib citrate | Metabolism, 62% in the urine (<3.5% as parent) and 22% in the feces (mainly as active metabolite ixazomib) | CYP3A,a CYP1A2, CYP2B6, CYP2C8, CYP2D6, CYP2C19, CYP2C9 | P-gp | FDA (2015s) |
| Alectinib | Metabolism, biliary excretion, 98% in the feces (84% as parent) and <0.5% in the urine | CYP3A4,a CYP2B6, CYP2C8, CYP2C9, CYP2D6 | P-gp | FDA (2015b) |
| Sugammadex | Mainly renal excretion, metabolism (<5%) | N/T (not likely to be metabolized by P450s or the liver) | N/T | FDA (2015e) |
| Selexipag | Metabolism, 93% in the feces and 12% in the urine | Carboxyesterase 1,a CYP2C8,a CYP3A4, UGT1A3, UGT2B7 | P-gp, OATP1B1/3 | FDA (2015z) |
| Lesinurad | Metabolism, 63% in the urine and 32% in the feces (64% as metabolites in both and 31% was excreted in urine as parent) | CYP2C9,a CYP1A1, CYP2C19, CYP3A, epoxide hydrolase | OAT1/3, OATP1B1/3, OCT1, BCRP | FDA (2015zg) |
BSEP, bile salt export pump; N/T, not tested.
↵a Primary enzymes responsible for metabolism of the respective NME.
↵b Results are based on published literature presented in the NDA review package.
↵c Eluxadoline was not metabolized based on in vitro studies but metabolism could not be ruled out according to the sponsor; more in vitro evaluations for eluxadoline as a substrate were requested as a PMR.
↵d Only P-gp and BCRP were tested.