Enzymes and transporters involved in the NDA elimination pathways

Compound NameMain Elimination RouteEnzyme InvolvedTransporter InvolvedReference
EdoxabanMinimal metabolism, 62% in the urine and 35% in the feces renal (primarily as parent in both)Carboxyesterase 1, phase II conjugation, CYP3AP-gp, OATP1B1FDA (2015w)
PalbociclibMetabolism, 74.1% in the feces and 17.5% in the urine (percentage of parent versus metabolites not available)CYP3A,a SULT2A1P-gp, BCRPFDA (2015n)
LenvatinibMetabolism, 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 biotransformationP-gp, BCRPFDA (2015q)
PanobinostatMetabolism, 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, UGT2B4P-gpFDA (2015l)
Ceftazidime (and avibactam)Not metabolized in the liver, renal excretion, 97% in the urine (80%–90% as parent)NoneOAT1, OAT3FDA (2015d)
Isavuconazonium sulfateMetabolism, 46% in the feces and 46% in the urine (active isavaconazole <1%)Esterases,a CYP3A4,a CYP3A5,a UGTsNoneFDA (2015i)
Cholic acidJoins 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 acidCYP3A4, UGT2A1 and UGT2A2bBSEP, BCRPbDeo and Bandiera (2008); Blazquez et al. (2012); Perreault et al. (2013); FDA (2015f)
IvabradineMetabolism, metabolites 37% in the urine and 47% in the feces (4% as parent in each)CYP3A4aP-gpFDA (2015g)
Deoxycholic acidNot metabolized, excreted in the feces as parentNoneBSEPFDA (2015p)
EluxadolineNot metabolized, 82% in the feces and 0.12% in the urine (percentage of parent versus metabolites not assessed)NonecOAT3, OATP1B1, BSEP, MRP2FDA (2015zc)
CangrelorMetabolism in plasma, 58% in the urine and 35% in the fecesNucleotidasesaN/TFDA (2015o)
Lumacaftor (and ivacaftor)Not extensively metabolized, biliary excretion, 51% in the feces as parentMainly via oxidation and glucuronidation enzymesN/TFDA (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)EsterasesaP-gp; LBQ657: OATP1B1/3, OAT3FDA (2015k)
BrexpiprazoleMetabolism, 46% in the feces (14% as parent) and 25% in the urine (parent <1%)CYP3A4,a CYP2D6aP-gp, BCRPFDA (2015v)
SonidegibMetabolism, 70% in the feces and 30% in the urineCYP3AaNoneFDA (2015t)
DaclatasvirMetabolism, biliary excretion, 88% in the feces (53% as parent), 6.6% in the urine (primarily as parent)CYP3A,a CYP2C8P-gpFDA (2015j)
FlibanserinMetabolism, 51% in the feces and 44% in the urineCYP3A4,a CYP2C19aNonedFDA (2015a)
RolapitantMetabolism, biliary excretion, 73% in the feces (mainly as parent)and 14% in the urine (primarily as metabolites)CYP3A4aNoneFDA (2015za)
Uridine triacetateMetabolism and catabolism, renal excretionEsterasesaP-gp, nucleoside transportersFDA (2015ze)
CariprazineMetabolism, 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 enzymesNoneFDA (2015zf)
Trifluridine (and tipiracil)Not metabolized, mainly renal excretion as parent, no mass balance studyNoneN/TFDA (2015r)
Insulin delgudecProteolytic degradationN/T, mostly by proteolytic enzymesN/TFDA (2015y)
Aripiprazole lauroxilHepatic metabolismParent: esterase-a and water-mediated hydrolysis,a aripiprazole: CYP3A4a and CYP2D6aN/TFDA (2015c)
PatiromerNot absorbed or metabolized, entirely excreted in the fecesN/T (not likely to be metabolized)N/TFDA (2015zb)
TrabectedinMetabolism, 58% in the feces and 6% in the urine (negligible as parent in each)CYP3A4,a other P450s (not specified)P-gpFDA (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, OATP1B1/3FDA (2015m)
CobimetinibMetabolism, 76% in the feces (6.6% as parent) and 18% in the urine (1.6% as parent)CYP3A, UGT2B7P-gpFDA (2015h)
OsimertinibMetabolism, 68% in the feces and 14% in urine (2% as parent overall in both)CYP3AaP-gp, BCRPFDA (2015x)
Ixazomib citrateMetabolism, 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, CYP2C9P-gpFDA (2015s)
AlectinibMetabolism, biliary excretion, 98% in the feces (84% as parent) and <0.5% in the urineCYP3A4,a CYP2B6, CYP2C8, CYP2C9, CYP2D6P-gpFDA (2015b)
SugammadexMainly renal excretion, metabolism (<5%)N/T (not likely to be metabolized by P450s or the liver)N/TFDA (2015e)
SelexipagMetabolism, 93% in the feces and 12% in the urineCarboxyesterase 1,a CYP2C8,a CYP3A4, UGT1A3, UGT2B7P-gp, OATP1B1/3FDA (2015z)
LesinuradMetabolism, 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 hydrolaseOAT1/3, OATP1B1/3, OCT1, BCRPFDA (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.