Table 3.

Examples of the metabolic activation of drugs by human cytochrome P450 enzymes

Drug	P450	Category	Reaction	PMIDs	References
Acetaminophen (paracetamol)	3A4	Analgesic, antipyretic	Oxidation to N-acetyl-p-benzoquinone imine (NABQI), activation, major at toxic concentrations	9152386, 7956731, 8374050, 2729995, 8380689, 10741631, 10872641, 9633991, 9246016, 15576447, 17894464, 19219744	(Cameron et al. 2007; Cheung et al. 2005b; Laine et al. 2009; Li et al. 1994; Manyike et al. 2000; Patten et al. 1993; Raucy et al. 1989; Roe et al. 1993; Sarich et al. 1997; Sinclair et al. 1998; Thummel et al. 2000; Zhou et al. 1997)
Acetaminophen (paracetamol)	2E1	Analgesic, antipyretic	Oxidation to NABQI, high Km, high activity, major in vivo enzyme, activation	9152386, 8374050, 2729995, 8380689, 10741631, 10872641, 9633991, 9246016, 15576447, 9056059, 8354023, 15532721, 31024054, 19219744, 9548799, 11095574, 11866476	(Bai and Cederbaum 2004; Chen et al. 1998; Cheung et al. 2005b; Dong et al. 2000; Hazai et al. 2002; Laine et al. 2009; Manyike et al. 2000; O’Shea et al. 1997; Patten et al. 1993; Rahman et al. 2019; Raucy et al. 1989; Roe et al. 1993; Sarich et al. 1997; Sinclair et al. 1998; Thummel et al. 2000; Zand et al. 1993; Zhou et al. 1997)
Acetaminophen (paracetamol)	2D6	Analgesic, antipyretic	Oxidation to NABQI, high Km, low to medium activity, activation	9152386, 9548799, 11095574, 11866476, 19219744	(Chen et al. 1998; Dong et al. 2000; Hazai et al. 2002; Laine et al. 2009; Zhou et al. 1997)
Acetaminophen (paracetamol)	1A2	Analgesic, antipyretic	Oxidation to NABQI, low to medium activity, activation	9152386, 7956731, 8374050, 2729995, 8380689, 10741631, 10872641, 9633991, 9246016, 15576447, 19219744	(Cheung et al. 2005b; Laine et al. 2009; Li et al. 1994; Manyike et al. 2000; Patten et al. 1993; Raucy et al. 1989; Roe et al. 1993; Sarich et al. 1997; Sinclair et al. 1998; Thummel et al. 2000; Zhou et al. 1997)
Acetaminophen (paracetamol)	2A6	Analgesic, antipyretic	Oxidation to NABQI, minor reaction, activation	9548799, 11095574, 11866476, 19219744	(Chen et al. 1998; Dong et al. 2000; Hazai et al. 2002; Laine et al. 2009)
Aminoflavone, NSC 68628	1A2	Anticancer, antiproliferative, flavone derivative	Hydroxylation, N4’-, N-5, activation	16775196, 12065765	(Chen et al. 2006a; Kuffel et al. 2002)
Aminoflavone, NSC 68628	1A1	Anticancer, antiproliferative, flavone derivative	Hydroxylation, N4’-, N5-, activation	12065765, 15210858, 16775196, 12065765	(Chen et al. 2006a; Kuffel et al. 2002; Loaiza-Pérez et al. 2004)
Aminoflavone, NSC 68628	2C9	Anticancer, antiproliferative, flavone derivative	Hydroxylation, N5-, activation,	16775196	(Chen et al. 2006a)
Aminoflavone, NSC 68628	2C19	Anticancer, antiproliferative, flavone derivative	Hydroxylation, N5- (activation, major enzyme at high conc.)	16775196	(Chen et al. 2006a)
Banoxantrone; 1,4-bis([2-(dimethylamino)ethyl]amino)-5,8-hydroxy-anthracene-9,10-dione bis-N-oxide (AQ4N)	1A1	Anticancer, anthraquinone prodrug	Reduction to AQ4, activation	12214668, 16410820	(Patterson 2002; Yakkundi et al. 2006)
AQ4N	1A2	Anticancer, anthraquinone prodrug	Reduction to AQ4, activation	12214668	(Patterson 2002)
AQ4N	1B1	Anticancer, anthraquinone prodrug	Reduction to AQ4, activation	12214668	(Patterson 2002)
AQ4N	2B6	Anticancer, anthraquinone prodrug	Reduction to AQ4, activation	15712360, 16410820	(McErlane et al. 2005; Yakkundi et al. 2006)
AQ4N	3A4	Anticancer, anthraquinone prodrug	Reduction to AQ4, activation	9845092, 10834269, 12214668, 12489027	(McCarthy et al. 2003; Patterson 2002; Patterson et al. 1999; Raleigh et al. 1998)
AQ4N	2S1	Anticancer, anthraquinone prodrug	Reduction to AQ4, activation	20566689, 21430234	(Nishida et al. 2010; Xiao et al. 2011)
AQ4N	2W1	Anticancer, anthraquinone prodrug	Reduction to AQ4, activation	20566689	(Nishida et al. 2010)
Carbamazepine	1A2	Antiepileptic	Activation	11760814, 9630846	(Masubuchi et al. 2001; Wolkenstein et al. 1998)
Carbamazepine	3A4	Antiepileptic	Activation	9630846	(Wolkenstein et al. 1998)
Carbamazepine, C2-hydroxy	3A4	Antiepileptic, carbamazepine metabolite	Iminostilbene formation (activation, major enzyme)	16135660	(Pearce et al. 2005)
Carbamazepine, C2-hydroxy	2C19	Antiepileptic, carbamazepine metabolite	Iminostilbene formation (activation, minor enzyme)	16135660, 18463198	(Pearce et al. 2008; Pearce et al. 2005)
Carbamazepine, C2-hydroxy	2D6	Antiepileptic, carbamazepine metabolite	Iminostilbene formation (activation, minor enzyme), at high concentration	16135660	(Pearce et al. 2005)
Carbamazepine, C3-hydroxy	3A5	Antiepileptic, carbamazepine metabolite	Hydroxylation, C2- (aromatic), activation	18463198	(Pearce et al. 2008)
Carbamazepine, C3-hydroxy	3A7	Antiepileptic, carbamazepine metabolite	Hydroxylation, C2- (aromatic), activation	18463198	(Pearce et al. 2008)
Carbamazepine, C3-hydroxy	2C19	Antiepileptic, carbamazepine metabolite	Hydroxylation, C2- (aromatic), activation, high activity	18463198	(Pearce et al. 2008)
Carbamazepine, C3-hydroxy	3A4	Antiepileptic, carbamazepine metabolite	Hydroxylation, C2- (aromatic), activation, major enzyme	18463198	(Pearce et al. 2008)
Carbamazepine, C3-hydroxy	1A1	Antiepileptic, carbamazepine metabolite	Hydroxylation, C2- (aromatic), activation, minor enzyme	18463198	(Pearce et al. 2008)
Carbamazepine, C3-hydroxy	1A2	Antiepileptic, carbamazepine metabolite	Hydroxylation, C2- (aromatic), activation, minor enzyme	18463198	(Pearce et al. 2008)
Carbamazepine, C3-hydroxy	2C18	Antiepileptic, carbamazepine metabolite	Hydroxylation, C2- (aromatic), activation, minor enzyme	18463198	(Pearce et al. 2008)
Clopidogrel	2C9	Antiplatelet, P2Y12 antagonist (thiophene)	Activation	19812348	(Kazui et al. 2010)
Clopidogrel	2B6	Antiplatelet, P2Y12 antagonist (thiophene)	Oxidation (2-oxo formation), low activity, or no activity, activation	12485953, 19812348, 26654298	(Clarke and Waskell 2003; Kazui et al. 2010; Zhai et al. 2016)
Clopidogrel	3A4	Antiplatelet, P2Y12 antagonist (thiophene)	Oxidation (2-oxo formation), major enzyme, activation	12485953, 10331074, 23770199, 19812348	(Clarke and Waskell 2003; Guengerich 1999; Kazui et al. 2010; Zahno et al. 2013)
Clopidogrel	2C19	Antiplatelet, P2Y12 antagonist (thiophene)	Oxidation (2-oxo formation), medium activity, activation	17682072, 19812348, 26654298	(Kazui et al. 2010; Walsky and Obach 2007; Zhai et al. 2016)
Clopidogrel	1A2	Antiplatelet, P2Y12 antagonist (thiophene)	Oxidation (2-oxo formation), very low to medium activity, activation	12485953, 19812348	(Clarke and Waskell 2003; Kazui et al. 2010)
Cyclophosphamide	3A7	Anticancer, alkylating, oxazaphosporine	N-Dechloroethylation (high Km, medium activity), activation to neuro- and nephrotoxic metabolite	15919850	(Chen et al. 2005)
Cyclophosphamide	3A4	Anticancer, alkylating, oxazaphosporine	N-Dechloroethylation (major enzyme, major reaction, high Km, high activity), activation to neuro- and nephrotoxic metabolite	8242617, 9010702, 9331082, 10692561, 15919850	(Bohnenstengel et al. 1996; Chang et al. 1993; Chen et al. 2005; Huang et al. 2000; Ren et al. 1997)
Cyclophosphamide	3A4	Anticancer, alkylating, oxazaphosporine	C4-Hydroxylation (high Km, high activity), activation to cytotoxic metabolite, major enzyme at high concentration	8242617, 9010702, 9331082, 9157990, 10348794, 10991840, 10692561, 9923542	(Bohnenstengel et al. 1996; Chang et al. 1993; Chang et al. 1997; Huang et al. 2000; Philip et al. 1999; Ren et al. 1997; Roy et al. 1999b; Zhou et al. 2000)
Cyclophosphamide	3A7	Anticancer, alkylating, oxazaphosporine	C4- Hydroxylation (high Km, low to high activity, major reaction), activation to cytotoxic metabolite	10348794, 15919850;9157990	(Chen et al. 2005; Roy et al. 1999b; Chang et al. 1997)
Cyclophosphamide	2C18	Anticancer, alkylating, oxazaphosporine	C4-Hydroxylation (low Km, activation to cytotoxic metabolite)	8242617, 9010702, 9331082, 10348794, , 10692561, 9157990	(Bohnenstengel et al. 1996; Chang et al. 1993; Chang et al. 1997; Huang et al. 2000; Ren et al. 1997; Roy 199b)
Cyclophosphamide	2B6	Anticancer, alkylating, oxazaphosporine	C4-Hydroxylation (major enzyme, major reaction, high Km, high activity, activation to cytotoxic metabolite), genetic polymorphism influence	8242617, 9010702, 9331082, 9157990, 10348794, 10991840, 10692561, 15919850, 10471061, 17502835, 11360624	(Bohnenstengel et al. 1996; Chang et al. 1993; Chang et al. 1997; Chen et al. 2005; Gervot et al. 1999; Huang et al. 2000; Nakajima et al. 2007; Ren et al. 1997; Roy et al. 1999b; Wu et al. 1997)
Dacarbazine	1A1	Anticancer, alkylating, imidazole carboxamide	N-Demethylation (major enzyme, activation)	10473105, 27428168	(Lewis et al. 2016; Reid et al. 1999)
Dacarbazine	1A2	Anticancer, alkylating, imidazole carboxamide	N-Demethylation (major enzyme, activation)	10473105, 27428168	(Lewis et al. 2016; Reid et al. 1999)
Dacarbazine	2E1	Anticancer, alkylating, imidazole carboxamide	N-Demethylation (activation, at higher concentration)	10473105	(Reid et al. 1999)
Dapsone	2B6	Antileprotic	Activation, minor contribution	19998329	(Ganesan et al. 2010)
Dapsone	2D6	Antileprotic	Activation, minor contribution	19998329	(Ganesan et al. 2010)
Dapsone	3A4	Antileprotic	N-Hydroxylation, (high Km, activation or no activity)	7586950, 8703658, 8181193, 8742227, 1588928, 19998329	(Fleming et al. 1992; Ganesan et al. 2010; Gill et al. 1995; Irshaid et al. 1996; May et al. 1994; Mitra et al. 1995)
Dapsone	2C8	Antileprotic	N-Hydroxylation, (high Km, minor enzyme), activation	10901692, 19998329	(Ganesan et al. 2010; Winter et al. 2000)
Dapsone	2C19	Antileprotic	N-Hydroxylation, (high Km, minor reaction), major enzyme for activation	10901692	(Winter et al. 2000)
Dapsone	2E1	Antileprotic	N-Hydroxylation, (low Km, activation), or no activity	7586950, 8703658, 8181193, 8742227, 1588928, 10901692	(Fleming et al. 1992; Gill et al. 1995; Irshaid et al. 1996; May et al. 1994; Mitra et al. 1995; Winter et al. 2000)
Dapsone	2C18	Antileprotic	N-Hydroxylation, (medium Km, minor reaction), activation	10901692	(Winter et al. 2000)
Dapsone	2C9	Antileprotic	N-Hydroxylation (medium Km, activation)	7586950, 8703658, 10901692, 9521735, 12920490	(Gill et al. 1995; Korzekwa et al. 1998; Li et al. 2003; Mitra et al. 1995; Winter et al. 2000)
Desogestrol	3A4	Estrogen, contraceptive	Oxygenation, mechanism-based inhibition	2133086, 2256525	{Guengerich, 1990, 12562; Guengerich, 1990, 13522}
Diclofenac	2C9	NSAID, cyclooxygenase-2 (COX-2) inhibitor	C4’-Hydroxylation, formation of 1´,4´-benzoquinoneimine (low or medium Km, medium or high activity, high efficiency, major enzyme, major reaction), activation	9698079, 8417277, 10027801, 10027798, 10950847, 10572000, 10449188, 12464247, 27130197, 19022234	(Bort et al. 1999; den Braver et al. 2016; Leemann et al. 1993; Mancy et al. 1999; Melet et al. 2003; Ngui et al. 2000; Shen et al. 1999; Tang et al. 1999; Yamazaki et al. 1998a)
Diclofenac	3A4	NSAID, COX-2 inhibitor	C5-Hydroxylation (major enzyme, high Km), reaction at high concentration (>100 μM), formation of proposed reactive intermediate	8417277, 10027801, 10027798, 10950847, 10572000, 12438516, 12871048, 17584015, 19022234	(Kalgutkar et al. 2007; Kumar et al. 2002; Lauer et al. 2009; Leemann et al. 1993; Mancy et al. 1999; Ngui et al. 2000; Shen et al. 1999; Tang 2003; Tang et al. 1999)
Diclofenac	3A4	NSAID, COX-2 inhibitor	C5-Hydroxylation, formation of 2,5-quinoneimine, activation	27130197	(den Braver et al. 2016)
Diclofenac 5-hydroxy	2C9	NSAID, COX-2 inhibitor	Activation, formation of 2,5-quinoneimine, activation	27130197	(den Braver et al. 2016)
Ellipticine	2B6	Anticancer, topoisomerase II inhibitor	C12-Hydroxylation, weak activation	11755121, 12123750, 22917556	(Frei et al. 2002; Stiborová et al. 2001a; Stiborová et al. 2012b)
Ellipticine	3A4	Anticancer, topoisomerase II inhibitor	C13- and C12-hydroxylation, activation (major enzyme)	11755121, 12123750, 15548707, 20027146, 22917556	(Frei et al. 2002; Martinkova et al. 2009:Stiborová, 2012b; Stiborová et al. 2001a; Stiborová et al. 2004)
Ellipticine	2C9	Anticancer, topoisomerase II inhibitor	C13- and C12-hydroxylation, activation, low activity	11755121, 12123750, 15548707, 22917556	(Frei et al. 2002; Stiborová et al. 2001a; Stiborová et al. 2012b; Stiborová et al. 2004)
Ellipticine	2D6	Anticancer, topoisomerase II inhibitor	C13- and C12-hydroxylation, activation, low activity	11755121, 12123750, 15548707, 22917556	(Frei et al. 2002; Stiborová et al. 2001a; Stiborová et al. 2012b; Stiborová et al. 2004)
Ellipticine	2E1	Anticancer, topoisomerase II inhibitor	C13- and C12-hydroxylation, activation, low activity	11755121, 12123750, 22917556	(Frei et al. 2002; Stiborová et al. 2001a; Stiborová et al. 2012b)
Ellipticine	2C19	Anticancer, topoisomerase II inhibitor	C13- and C12-hydroxylation, activation, low activity	11755121, 12123750, 15548707, 22917556	(Frei et al. 2002; Stiborová et al. 2001a; Stiborová et al. 2012b; Stiborová et al. 2004)
Ellipticine	1A1	Anticancer, topoisomerase II inhibitor	C13-Hydroxylation, activation	11755121, 12123750, 15548707, 22917556, 20027146	(Frei et al. 2002; Martinkova et al. 2009; Stiborová et al. 2001a; Stiborová et al. 2012b; Stiborová et al. 2004)
Ellipticine	1A2	Anticancer, topoisomerase II inhibitor	C13-Hydroxylation, activation, low activity	11755121, 12123750, 15548707, 22917556	(Frei et al. 2002; Stiborová et al. 2001a; Stiborová et al. 2012b; Stiborová et al. 2004)
Ellipticine	1B1	Anticancer, topoisomerase II inhibitor	C13-Hydroxylation, activation, low activity	11755121, 12123750, 22917556, 20027146	(Frei et al. 2002; Martinkova et al. 2009; Stiborová et al. 2001a; Stiborová et al. 2012b; Stiborová et al. 2004)
17α-Ethynylestradiol	3A4	Estrogen, contraceptive	Epoxidation (activation)	16251255	(Chen et al. 2006b)
17α-Ethynylestradiol	3A4	Estrogen, contraceptive	Oxygenation, mechanism-based inhibition	17251390, 17584015, 11907170, 3285175, 2133086, 2256525	(Guengerich 1988; Guengerich 1990a; Guengerich 1990b; Kalgutkar et al. 2007; Lin and Hollenberg 2007; Lin et al. 2002)
17α-Ethynylestradiol	3A5	Estrogen, Contraceptive	Oxygenation, mechanism-based inhibition	17251390, 17584015	(Kalgutkar et al. 2007; Lin and Hollenberg 2007)
Flutamide	2C9	Anticancer, antiandrogen, nonsteroidal, nitroaromatic	C2-Hydroxylation, activation	16507648	(Goda et al. 2006)
Flutamide	1B1	Anticancer, antiandrogen, nonsteroidal, nitroaromatic	C2-Hydroxylation (activation, major enzyme in cancer cells)	11160641	(Rochat et al. 2001)
Flutamide	1A2	Anticancer, antiandrogen, nonsteroidal, nitroaromatic	C2-Hydroxylation (activation, major enzyme)	8386241, 16507648, 9351907, 12052211, 18411402	(Berson et al. 1993; Goda et al. 2006; Kang et al. 2008; Patterson and Murray 2002; Shet et al. 1997)
Flutamide	1A2	Anticancer, antiandrogen, nonsteroidal, nitroaromatic	Amide oxidation, N-hydroxylation following amide cleavage	17403914, 18411402, 16507648	(Kang et al. 2007; Kang et al. 2008; Goda et al. 2006)
Flutamide	2C19	Anticancer, antiandrogen, nonsteroidal, nitroaromatic	Amide oxidation, N-hydroxylation following amide cleavage	17403914, 18411402, 16507648	(Kang et al. 2007; Kang et al. 2008; Goda et al. 2006)
Flutamide	3A4	Anticancer, antiandrogen, nonsteroidal, nitroaromatic	Amide oxidation, N-hydroxylation following amide cleavage	16507648	(Kang et al. 2007)
Gestodene	3A4	Estrogen, contraceptive	Oxygenation, mechanism-based inhibition, hydroxylation	2133086, 2256525, 8664172	(Guengerich 1990a; Guengerich 1990b; Ward and Back 1993)
Haloperidol	1A1	Antipsychotic, butyrophenone	Oxidation, pyridinium metabolite formation, activation	11717183, 16841959	(Avent et al. 2006; Fang et al. 2001)
Haloperidol	1B1	Antipsychotic, butyrophenone	Oxidation, pyridinium metabolite formation, activation	16841959	(Avent et al. 2006)
Haloperidol	2D6	Antipsychotic, butyrophenone	Oxidation, pyridinium metabolite formation, activation	9140699, 9844810	(Fang et al. 1997; Usuki et al. 1998)
Haloperidol	3A5	Antipsychotic, butyrophenone	Oxidation, pyridinium metabolite formation, activation	9140699, 9844810, 9431831, 10628896, 12584149, 11167668, 16841959	(Avent et al. 2006; Fang et al. 1997; Kalgutkar et al. 2003; Kudo and Ishizaki 1999; Pan et al. 1997; Shin et al. 2001; Usuki et al. 1998)
Haloperidol	3A7	Antipsychotic, butyrophenone	Oxidation, pyridinium metabolite formation, activation	16841959	(Avent et al. 2006)
Haloperidol	3A4	Antipsychotic, butyrophenone	Oxidation, pyridinium metabolite formation, activation	9140699, 9844810, 9431831, 10628896, 12584149, 11167668, 11717183, 24913773	(Fang et al. 1997; Fang et al. 2001; Kalgutkar et al. 2003; Kudo and Ishizaki 1999; Kurth et al. 2014; Pan et al. 1997; Shin et al. 2001; Usuki et al. 1998)
Haloperidol	3A4	Antipsychotic, butyrophenone	Oxidation, pyridinium metabolite formation, activation	9431831, 10628896, 12584149, 11167668, 11717183, 24913773	(Fang et al. 2001; Kalgutkar et al. 2003; Kudo and Ishizaki 1999; Kurth et al. 2014; Pan et al. 1997; Shin et al. 2001)
Halothane	2E1	General inhalation anesthetic, haloalkane	Dehalogenation, oxidative, activation (major reaction, major enzyme in vivo, low Km)	9616199, 9103523, 8886607, 10805064, 11506127, 11684364, 17584015, 24913773	(Kalgutkar et al. 2007; Kharasch et al. 2000; Kurth et al. 2014; Minoda and Kharasch 2001; Spracklin et al. 1997; Spracklin and Kharasch 1998; Spracklin et al. 1996; White and De Matteis 2001)
Halothane	2A6	General inhalation anesthetic, haloalkane	Dehalogenation, oxidative, activation (minor reaction, high Km)	9616199, 9103523, 8886607, 10805064, 11506127, 24913773	(Kalgutkar et al. 2007; Kharasch et al. 2000; Kurth et al. 2014; Spracklin et al. 1997; Spracklin and Kharasch 1998; Spracklin et al. 1996)
Halothane	3A4	General inhalation anesthetic, haloalkane	Dehalogenation, reductive, activation (high Km)	9616199, 9103523, 8886607, 10805064, 11506127, 24913773	(Kalgutkar et al. 2007; Kharasch et al. 2000; Kurth et al. 2014; Spracklin et al. 1997; Spracklin and Kharasch 1998; Spracklin et al. 1996)
Halothane	2A6	General inhalation anesthetic, haloalkane	Dehalogenation, reductive, activation (low Km)	9616199, 9103523, 8886607, 10805064, 11506127, 24913773	(Driscoll et al. 2007; Kharasch et al. 2000; Kurth et al. 2014; Spracklin et al. 1997; Spracklin and Kharasch 1998; Spracklin et al. 1996)
Halothane	2B6	General inhalation anesthetic, haloalkane	Oxidation, activation	11684364, 24913773	(Kalgutkar et al. 2007; White and De Matteis 2001)
Halothane	2E1	General inhalation anesthetic, haloalkane	Oxidation, activation	11684364, 24913773	(Kalgutkar et al. 2007; White and De Matteis 2001)
Ifosfamide, (R)-	3A5	Anticancer, alkylating, oxazaphosporine	Hydroxylation, C4, activation to cytotoxic product	10348794, 15821045, 10534317, 16854777	(Lu et al. 2006; McCune et al. 2005; Roy et al. 1999a)
Ifosfamide, (R)-, (S)-	3A4	Anticancer, alkylating, oxazaphosporine	Dechloroethylation, N2-, N3- (high Km, high activity, major enzyme, major reaction for (S)-), activation to neuro- and nephrotoxic metabolites	8242617, 10692561, 15919850, 15821045, 16854777, 10534317, 8161344, 8071856, 10101149, 9923542, 17464949	(Chang et al. 1993; Chen et al. 2005; Chugh et al. 2007; Granvil et al. 1999; Huang et al. 2000; Lu et al. 2006; McCune et al. 2005; Murray et al. 1994; Philip et al. 1999; Roy et al. 1999a; Walker et al. 1994)
Ifosfamide, (R)-, (S)-	2B6	Anticancer, alkylating, oxazaphosporine	Dechloroethylation, N2-, N3- (high Km, high activity, major enzyme, major reaction), activation to neuro- and nephrotoxic metabolites.	10692561, 15919850, 15821045, 16854777, 10534317	(Chen et al. 2005; Huang et al. 2000; Lu et al. 2006; McCune et al. 2005; Roy et al. 1999a)
Ifosfamide, (R)-, (S)-	2C9	Anticancer, alkylating, oxazaphosporine	Hydroxylation, C4- (low Km), activation to cytotoxic metabolites	8242617, 9157990	(Chang et al. 1993; Chang et al. 1997)
Ifosfamide, (S)-	2B6	Anticancer, alkylating, oxazaphosporine	Hydroxylation, C4- (high Km, medium (R-) and high (S-) activity, major enzyme), activation to cytotoxic metabolites	8242617, 10348794, 10692561, 9157990, 15919850, 25934575	(Calinski et al. 2015; Chang et al. 1993; Chang et al. 1997; Huang et al. 2000; Roy et al. 1999a)
Isoniazid	2E1	Antituberculotic, pyridine	Oxidation, activation, major enzyme	12668988, 18071298	(Huang et al. 2003; Shen et al. 2008)
3-Ketodesogestrol	3A4	Estrogen, contraceptive	Oxygenation, mechanism-based inhibition	2133086, 2256525	(Guengerich 1990a; Guengerich 1990b)
Levonorgestrol	3A4	Estrogen, contraceptive	Oxygenation, mechanism-based inhibition	2133086, 2256525	(Guengerich 1990a; Guengerich 1990b)
Norethisterone	3A4	Estrogen, contraceptive	Oxygenation, mechanism-based inhibition	2133086, 2256525	(Guengerich 1990a; Guengerich 1990b)
Phencyclidine	2B6	Hallucinogenic (angel dust, angel hair, angel mist), analgesic and anesthetic	C-Hydroxylation, (p-hydroxy and quinone methide formation), activation	17892269, 16326815, 16782764	(Driscoll et al. 2007; Jushchyshyn et al. 2006; Shebley et al. 2006)
Phencyclidine	2C19	Hallucinogenic (angel dust, angel hair, angel mist), analgesic and anesthetic	C-Hydroxylation (p-hydroxy and quinone methide formation), activation	17892269, 16326815, 16782764	(Driscoll et al. 2007; Jushchyshyn et al. 2006; Shebley et al. 2006)
Raloxifene	2D6	Anticancer and prevention of osteoporosis, antiestrogen, estrogen receptor modulator, benzothiophene	Oxidation, activation, minor enzyme	12119000	(Chen et al. 2002)
Raloxifene	3A4	Anticancer and prevention of osteoporosis, antiestrogen, estrogen receptor modulator, benzothiophene	3´-Hydroxylation, oxidation, glutathione (GSH) adduct formation, activation	12119000, 18052110, 17497897, 17584015, 20405834	(Baer et al. 2007; Chen et al. 2002; Hollenberg et al. 2008; Kalgutkar et al. 2007; Moore et al. 2010a)
Raloxifene	3A4	Anticancer and prevention of osteoporosis, antiestrogen, estrogen receptor modulator, benzothiophene	Dehydrogenation, activation, reactive diquinonemethide and 7-hydroxyraloxifene formation	20405834, 20812728, 17867646, 12119000	(Chen et al. 2002; Moore et al. 2010a; Moore et al. 2010b; Yukinaga et al. 2007)
Tamoxifen	1A1	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	Hydroxylation, C3-, C4- (catechol formation, activation)	10348797, 8293548, 12018981, 12124303, 12419838, 12623757	(Boocock et al. 2002; Crewe et al. 2002; Dehal and Kupfer 1999; Hu et al. 2003; Notley et al. 2002; Styles et al. 1994)
Tamoxifen	3A5	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	Hydroxylation, C3-, C4- (catechol formation, activation)	10348797, 8293548, 12018981, 12124303, 12419838, 12623757	(Boocock et al. 2002; Crewe et al. 2002; Dehal and Kupfer 1999; Hu et al. 2003; Notley et al. 2002; Styles et al. 1994)
Tamoxifen	3A5	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	Cα-Hydroxylation, activation, at high concentration (250 μM)	15159443, 16533026	(Desta et al. 2004; Notley et al. 2005)
Tamoxifen	3A4	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	Cα-Hydroxylation (major enzyme, activation), at low and high concentrations (18 and 250 μM)	10348797, 8293548, 12018981, 12124303, 12419838, 12623757, 16533026, 15159443, 14678348, 12971802	(Boocock et al. 2002; Coller et al. 2004; Crewe et al. 2002; Dehal and Kupfer 1999; Desta et al. 2004; Hu et al. 2003; Kim et al. 2003; Notley et al. 2005; Notley et al. 2002; Styles et al. 1994)
Tamoxifen	2B6	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	Oxidation, activation	12061800, 7748182	(Stiborová et al. 2002; White et al. 1995)
Tamoxifen	3A4	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	Oxidation, activation	7748182	(White et al. 1995)
Tamoxifen, 3-hydroxy (droloxifene)	2D6	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	C4-Hydroxylation, (catechol form., low extent, activation)	10348797	(Dehal and Kupfer 1999)
Tamoxifen 3-hydroxy, (droloxifene)	3A4	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine	C4-Hydroxylation, (catechol formation, major reaction, activation)	10348797	(Dehal and Kupfer 1999)
Tamoxifen, 4-hydroxy	3A4	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine, tamoxifen metabolite	N-Demethylation, activation, formation of major antiestrogenic metabolite	15159443	(Desta et al. 2004)
Tamoxifen, 4-hydroxy	2D6	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine, tamoxifen metabolite	C3-Hydroxylation (catechol formation, low extent, activation)	10348797	(Dehal and Kupfer 1999)
Tamoxifen, 4-hydroxy	3A4	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine, tamoxifen metabolite	C3-Hydroxylation (catechol formation, major reaction, activation)	10348797, 15159443	(Dehal and Kupfer 1999; Desta et al. 2004)
Tamoxifen, N-desmethyl	2D6	Anticancer, antiestrogen, estrogen receptor modulator, triphenylethyleneamine, tamoxifen metabolite	C4-Hydroxylation (major enzyme, activation), formation of major antiestrogenic metabolite, genetic polymorphism influences clinical response, proposed clinically significant drug-drug interaction potential when inhibited	14652237, 15159443, 15111773, 16815318, 17518364, 23711794, 30536272, 29637493, 26423799	(Beverage et al. 2007; Bezerra et al. 2018; Borges et al. 2006; Desta et al. 2004; Hansten 2018; Johnson et al. 2004; Stearns et al. 2003; Watanabe et al. 2015; Yang et al. 2013)
Thiabendazole	1A1	Antifungal, benzimidazole	C5-Hydroxylation, activation,	12920490	(Li et al. 2003)
Thiabendazole	1A2	Antifungal, benzimidazole	C5-Hydroxylation (activation, major enzyme)	10936227, 9565779, 12920490	(Coulet et al. 1998; Coulet et al. 2000; Li et al. 2003)
Thiabendazole	1B1	Antifungal, benzimidazole	C5-Hydroxylation, activation,	12920490	(Li et al. 2003)
Tienilic acid	2C9	Diuretic and uricosuric, 2-aroylthiophene	Epoxidation (thiophene ring), activation, proposed reactive intermediate formation in mechanism-based inhibition process	8286335, 8075377, 17584015, 8477697	(Kalgutkar et al. 2007; Lecoeur et al. 1994; Lopez Garcia et al. 1993; López-Garcia et al. 1994)
Tienilic acid	2C9	Diuretic and uricosuric, 2-aroylthiophene	Oxidation, S-oxygenation (thiophene ring), activation, proposed reactive intermediate formation in mechanism-based inhibition process	17584015	(Kalgutkar et al. 2007)
Tolcapone, acetylamine	1A2	Dopaminergic, catechol-O-methyltransferase (COMT) inhibitor, tolcapone metabolite	Oxidation, activation, major enzyme	10806608, 12588182	(Jorga et al. 2000; Smith et al. 2003b)
Tolcapone, amine	1A2	Dopaminergic, COMT inhibitor, tolcapone metabolite	Oxidation, activation, major enzyme	10806608, 12588182	(Jorga et al. 2000; Smith et al. 2003b)
Tolmetin	3A4	Analgesic, anti-inflammatory	Epoxidation, activation	16251255	(Chen et al. 2006b)
Toremifene	3A4	Antiestrogen, estrogen receptor modulator, triphenylethylene	Cα-Hydroxylation, activation	12971802, 26423799	(Kim et al. 2003; Watanabe et al. 2015)
Toremifene, N-desmethyl	2C9	Antiestrogen, estrogen receptor modulator, triphenylethylene	4-Hydroxylation, endoxifen formation, activation	26423799	(Watanabe et al. 2015)
Toremifene, N-desmethyl	2D6	Antiestrogen, estrogen receptor modulator, triphenylethylene	4-Hydroxylation, activation	26423799	(Watanabe et al. 2015)
N,Ń,N´´-Triethylene thiophosphoramide (ThioTEPA)	3A4	Anticancer, alkylating agent, aziridine	Desulfuration, N,Ń,N´´-triethylene phosphoramide (TEPA) formation (major enzyme, activation)	12107550, 19076156	(Ekhart et al. 2009; Jacobson et al. 2002)
ThioTEPA	2B6	Anticancer, alkylating agent, aziridine	Desulfuration, TEPA formation (minor enzyme, activation)	12107550, 15121764, 17584015, 19076156	(Ekhart et al. 2009; Harleton et al. 2004; Jacobson et al. 2002; Kalgutkar et al. 2007)
ThioTEPA	1B1	Anticancer, alkylating agent, aziridine	Desulfuration, TEPA formation (minor enzyme, activation)	15121764	(Harleton et al. 2004)
Troglitazone	1A2	Peroxisome proliferation activation receptor (PPAR)-γ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring, activation	15155556	(He et al. 2004a)
Troglitazone	2C8	PPARγ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring, activation	10534310	(Yamazaki et al. 1999)
Troglitazone	2C19	PPARγ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring, activation	15155556	(He et al. 2004a)
Troglitazone	2D6	PPARγ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring, activation	15155556	(He et al. 2004a)
Troglitazone	2E1	PPARγ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring, activation	15155556	(He et al. 2004a)
Troglitazone	3A4	PPARγ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring, activation	15155556, 11511170, 11389877, 10534310, 11170509	(He et al. 2004a; He et al. 2001; Kassahun et al. 2001; Tettey et al. 2001; Yamazaki et al. 1999)
Troglitazone	3A5	PPARγ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring, activation	15155556	(He et al. 2004a)
Troglitazone	2C8	PPARγ agonist, thiazolidinedione, glitazone	Oxidation of thiazolidinedione ring (activation, major enzyme)	15155556	(He et al. 2004a)
Valproic acid	2A6	Antiepileptic, histone deacetylase (HDAC) inhibitor	Dehydrogenation (desaturation, 4-ene formation, activation), minor enzyme	16945988, 10461547, 9353388	(Ekins and Wrighton 1999; Kiang et al. 2006; Sadeque et al. 1997)
Valproic acid	2C9	Antiepileptic, HDAC inhibitor	Dehydrogenation (desaturation, 4-ene formation, activation), major enzyme	16945988, 10461547, 9353388, 14597963	(Ekins and Wrighton 1999; Ho et al. 2003; Kiang et al. 2006; Sadeque et al. 1997)
Valproic acid	2B6	Antiepileptic, HDAC inhibitor	Dehydrogenation (desaturation, 4-ene formation, activation), minor enzyme	16945988, 10461547	(Ekins and Wrighton 1999; Kiang et al. 2006)