Enzymes and transporters involved in the NDA/BLA elimination pathways

Drug NameMain Elimination RouteEnzymes InvolvedaTransporters InvolvedaReference
Ado-trastuzumab emtansine (T-DM1)DM1: metabolism; no mass balance study for T-DM1T: Proteolytic enzymesb; DM1: CYP3A4b, CYP3A5bP-gpc(FDA, 2013l)
AfatinibMinimal metabolism, fecal (85% mostly as parent)Flavin monoooxygenaseb, cytochrome P450sP-gp, BCRPd(FDA, 2013i)
AlogliptinMinimal metabolism, renal (76% mainly as parent), fecal (13%)CYP2D6, CYP3A4Nonec(FDA, 2013q)
CanagliflozinMetabolism, fecal (60.4% mainly as parent), renal (32.5 mainly as metabolites)UGT2B4b, UGT1A9b, CYP3A4, CYP2D6P-gp, MRP2(FDA, 2013k)
Conjugated estrogens and bazedoxifeneE: metabolism, renal (as parents and metabolites); B: metabolism, fecal (85% mainly as parent)E: CYP3A4b; B: UGT1A1b, UGT1A10b, UGT1A8Not testede(FDA, 2013g)
DabrafenibMetabolism, fecal (71%), renal (23%)CYP2C8b, CYP3A4b, CYP2C9, CYP2C19P-gpc(FDA, 2013w)
Dimethyl fumarateMetabolism, exhalation of CO2 (60%), renal (15.5%)Esterasesb, tricarboxylic acid cycleb (non–cytochrome P450)Nonec(FDA, 2013x)
DolutegravirMetabolism, fecal (53% as parent), renal (31% mainly as metabolites)UGT1A1, UGT1A3, UGT1A9P-gp, BCRPd(FDA, 2013y)
Eslicarbazepine acetateMetabolism, renal (90% as parent and metabolites)Non–cytochrome P450 hydrolytic enzymesb, UGT1A9, UGT2B4, UGT2B17Not tested(FDA, 2013c)
Fluemetamol F-18Fecal (52%), renal (37%)Not availableNot tested(FDA, 2013z)
Fluticasone and vilanterolF: metabolism, fecal (90%); V: metabolism, renal (70%), fecal (30%)F: CYP3A4b; V:CYP3A4bF: P-gpb; V: P-gpb,c(FDA, 2013d)
Gadoterate meglumineRenal (86.6% as parent)NoneNot tested(FDA, 2013f)
IbrutinibMetabolism, fecal (80.6% mostly as metabolites)CYP3A4b, CYP2D6Nonec(FDA, 2013j)
LuliconazoleMetabolism (topical use)CYP2D6b, CYP3A4bNot tested(FDA, 2013n)
MacitentanMetabolism, renal (50% as inactive metabolites), fecal (24%)CYP3A4 (99%)b, CYP2C19None(FDA, 2013s)
MipomersenMetabolism in tissues, renal (< 2%)Endonucleases and exonucleasesb (non–cytochrome P450)Nonec(FDA, 2013m)
ObinutuzumabMinimal hepatic or renal eliminationProteolytic enzymesbNot tested(FDA, 2013h)
OspemifeneMetabolism, fecal (75% mainly as metabolites)CYP3A4 (40-55%)b, CYP2C9 (25%)b, CYP2C19 (25%)bNonec(FDA, 2013t)
PomalidomideMetabolism, renal (73% mainly as metabolites), fecal (15% mainly as metabolites)CYP1A2 (54%)b, CYP3A4 (30%)b, CYP2C19, CYP2D6, non–cytochrome P450 hydrolytic enzymesP-gpc(FDA, 2013u)
Radium Ra 223 dichlorideFecalNoneNot tested(FDA, 2013aa)
RiociguatMetabolism, fecal (53% mainly as metabolites), renal (40% mainly as metabolites)CYP1A1b, CYP3A, CYP2C8, CYP2J2P-gp, BCRPd(FDA, 2013a)
SimeprevirMetabolism, fecal (91% mainly in metabolites)CYP3A4b, CYP2C8, CYP2C19OATP1B1, OATP1B3, P-gp, MRP2, OATP2B1, mBcrpf(FDA, 2013r)
SofosbuvirMetabolism, 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 tilmanoceptNot availableNoneNot tested(FDA, 2013o)
TrametinibMinimal metabolism, fecal (50-75% as parent), renal (<20%)CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4, non–cytochrome P450 hydrolytic enzymesNoned(FDA, 2013p)
Umeclidinium and vilanterolU: metabolism, fecal (92% as parent and metabolites); V: metabolism, renal (70% as metabolites), fecal (30% as metabolites)U: CYP2D6b, CYP3A4, UGTs; V: CYP3A4b, CYP2D6U: P-gp, OCT1, OCT2, V: P-gp(FDA, 2013b)
VortioxetineMetabolism, fecal (59% as metabolites), renal (26% as metabolites)CYP2D6b, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, CYP2B6, UGTsNonec(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.