Table 1.
Overview of the currently used anticancer drugs, their metabolic pathways, and if genetic polymorphisms significantly alter their pharmacokinetics
| Anti-cancer drug | Target | Metabolizing enzymes | Transporters/receptors | Polymorphism-altering pharmacokinetics |
|---|---|---|---|---|
| Alkylating agents | ||||
| Bendamustine | DNA | CYP1A2 | No, mainly non-enzymatic | |
| Busulfan | DNA | CYP2C9, CYP2B6, GSTs | Yes [159, 160] | |
| Carmustine | DNA | Unknown | ||
| Chlorambucil | DNA | GSTs | Yes [161] | |
| Cyclophosphamide | DNA | CYP3A4, CYP3A5, CYP2B6, CYP2C19, GSTs | Yes [32, 162] | |
| Dacarbazine | DNA | CYP1A1, CYP1A2, CYP2E1 | Unknown | |
| Estramustine | DNA | Unknown | ||
| Hydroxycarbamide | DNA | Unknown | ||
| Ifosfamide | DNA | CYP2A6, CYP2B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTs | Yes [9, 162] | |
| Lomustine | DNA | Unknown | ||
| Mechlorethamine | DNA | Unknown | ||
| Melphalan | DNA | LAT1, LAT2 | No [163] | |
| Temozolomide | DNA | No, mainly non-enzymatic | ||
| Procarbazine | DNA | CYP2B6, CYP1A4, CYP3A5 | Unknown | |
| Thiotepa | DNA | CYP3A4,CYP3A5 CYP2B6 | Yes [9] | |
| Treosulfan | DNA | No, mainly non-enzymatic [160] | ||
| Antimetabolites | ||||
| Azacitidine | DNA/RNA | CDA | Yes [164] | |
| Capecitabine | DNA/RNA | DPD | Yes [70] | |
| Cladribine | DNA/RNA | dCK | Unknown | |
| Clofarabine | DNA/RNA | dCK | Yes [92, 93] | |
| Cytarabine | DNA/RNA | dCK | MDR1 | Yes [86] |
| Decitabine | DNA/RNA | CDA, dCK | Yes [90, 95] | |
| Fludarabine | DNA/RNA | dCK | Yes [91] | |
| Fluorouracil | DNA/RNA | DPD, GSTs | Yes [49] | |
| Gemcitabine | DNA/RNA | CDA, dCK | Yes [87–89] | |
| Mercaptopurine | DNA/RNA | TPMT | Yes [72, 73] | |
| Methotrexate | DNA/RNA | MTHFR | SLC, MDR1 | Yes [71, 81–84] |
| Nelarabine | DNA/RNA | Unknown | ||
| Pemetrexed | DNA/RNA | Unknown | ||
| Tegafur | DNA/RNA | DPD, CYP2A6, CYP2C8, CYP1A2 | Yes [57] | |
| Tioguanine | DNA/RNA | TPMT | Yes [165] | |
| Anti-mitotic cytostatics | ||||
| Cabazitaxel | Microtubule | CYP3A4 | Unknown | |
| Docetaxel | Microtubule | CYP1B1, CYP2B6, CYP3A4, CYP3A5 | MDR1, BCRP | Yes [98, 105] |
| Paclitaxel | Microtubule | CYP2C8, CYP3A4, CYP3A5 | MDR1, BCRP | Yes [98, 105] |
| Vinblastine | Microtubule | CYP3A4,CYP3A5, GSTs | Unknown | |
| Vincristine | Microtubule | CYP3A4,CYP3A5, GSTs | MDR1 | No [166] |
| Vinorelbine | Microtubule | CYP2D6, CYP2E1, CYP3A4,CYP3A5, GSTs | Unknown | |
| Anti-tumor antibacterials | ||||
| Bleomycin | DNA/RNA | BLMH, GSTs | Yes [167] | |
| Dactinomycin | DNA/RNA | GSTs | MDR1 | No [168] |
| Daunorubicin | DNA | GSTs | MDR1 | No [108] |
| Doxorubicin | DNA | CYP2B6, CYP3A4, CYP3A5, CYP2D6, GSTs, UGTs | MDR1, BCRP | Yes [106] |
| Epirubicin | DNA | UGTs | MDR1, SLC | No [107] |
| Idarubicin | DNA | CYP2D6, CYP2C9, GSTs | MDR1 | Unknown |
| Mitomycin | DNA | GSTs | Unknown | |
| Mitoxantrone | DNA | CYP1B1, CYP3A4, CYP3A5, GSTs | MDR1 | Unknown |
| Topoisomerase inhibitors | ||||
| Etoposide | Topoisomerase | CYP1A2, CYP2E1, CYP3A4, CYP3A5, GSTs, UGTs | MDR1 | Yes [98] |
| Irinotecan | Topoisomerase | CYP3A4, CYP3A5, UGTs | MDR1, BCRP | Yes [169] |
| Teniposide | Topoisomerase | CYP3A4, CYP3A5, UGTs | Unknown | |
| Topotecan | Topoisomerase | CYP3A4, CYP3A5, UGTs | BCRP | No [170] |
| Anti-hormones | ||||
| Abiraterone | Androgen receptor | Unknown | ||
| Anastrozole | Aromatase | CYP3A4, CYP3A5, CYP2C8, CYP19A1, UGTs | Yes [171] | |
| Bicalutamide | Androgen receptor UGTs | MDR1, BCRP | Yes [113] | |
| Enzalutamide | Androgen receptor | CYP2C8, CYP3A4, CYP3A5 | Unknown | |
| Exemestane | Aromatase | CYP3A4, CYP3A5, CYP4A11, CYP1A2, CYP19A1, UGTs | Yes [172] | |
| Flutamide | Aromatase | CYP1A2 | No [9] | |
| Letrozole | Aromatase | CYP3A4, CYP3A5, CYP2A6, CYP19A1 | Yes [172] | |
| Megestrol | Estrogen receptor | Unknown | ||
| Nilutamide | Androgen receptor | Unknown | ||
| Tamoxifen | Estrogen receptor | CYP2D6, CYP3A5, CYP3A4, CYP2C9, CYP2C19, CYP1B1, UGTs | Yes [173] | |
| Fulvestrant | Estrogen receptor | CYP3A4, CYP3A5 | No, mainly non-enzymatic | |
| Tyrosine kinase inhibitors | ||||
| Afatinib | EGFR | No, mainly non-enzymatic | ||
| Axitinib | VEGF-R 1-3 | CYP3A4, CYP1A2, CYP2C19, UGTs | MDR1 | No [125] |
| Bosutinib | BCR-ABL/SRc | CYP3A4 | MDR1 | No [115] |
| Crizotinib | ALK | CYP3A4, CYP3A5 | Unknown | |
| Dabrafenib | BRAF | CYP2C8, CYP3A4 | Unknown | |
| Dasatinib | BCR-ABL | CYP3A4 | MDR1, BCRP | No [115] |
| Erlotinib | EGFR | |||
| Gefetinib | EGFR | CYP3A4, CYP3A5, CYP2D6 | MDR1, BCRP | No [28] |
| Imatinib | BCR-ABL | CYP3A4, CYP3A5, CYP2C8 | MDR1, BCRP, SLC | Yes [118, 119] |
| Lapatinib | HER-2 | CYP3A4, CYP3A5, CYP2C19, CYP2C8 | Unknown | |
| Nilotinib | BCR-ABL | CYP3A4, CYP2C8 | BCRP, SLC | No [115] |
| Olaparib | PARP | CYP3A4 | Unknown | |
| Pazopanib | Multi | CYP3A4, CYP1A2, CYP2C8 | Unknown | |
| Ponatinib | BCR-ABL | CYP3A4 | No [115] | |
| Regorafenib | Multi | CYP3A4, UGTs | Unknown | |
| Ruxolitinib | JAK | CYP3A4, CYP2C9 | Unknown | |
| Sorafenib | Multi | CYP3A4, UGTs | BCRP | Yes [126] |
| Sunitinib | Multi | CYP3A4, CYP3A5 | MDR1, BCRP | Yes [174] |
| Vandetanib | Multi | CYP3A4 | Unknown | |
| Vemurafenib | BRAF | CYP3A4 | No, mainly non-enzymatic | |
| Biologicals | ||||
| Bevacizumab | VEGF | Unknown | ||
| Brentuximab | CD30 | CYP3A4, CYP2D6 | Unknown | |
| Cetuximab | EGFR | FCGRT | Yes [145–148] | |
| Ipilimumab | CTLA-4 | Unknown | ||
| Nivolumab | PD-1 | Unknown | ||
| Ofatumumab | CD20 | Unknown | ||
| Panitumumab | EGFR | Unknown | ||
| Pembrolizumab | PD-1 | Unknown | ||
| Pertuzumab | HER-2 | Unknown | ||
| Rituximab | CD20 | FCGRT | Yes [138–142] | |
| Trastuzumab | HER-2 | FCGRT | Yes [143, 144] | |
| Immunomodulants | ||||
| Lenalidomide | Bone marrow | No, mainly non-enzymatic | ||
| Pomalidomide | Bone marrow | CYP1A2, CYP3A4, CYP2C19, CYP2D6 | Unknown | |
| Thalidomide | Bone marrow | CYP2C19 | Yes [175] | |
| Non-categorized | ||||
| Asparaginase (PEG) | l-Asparagine | No [71] | ||
| Bortezomib | Proteasome | CYP3A4, CYP2C19, CYP1A2 | No [176] | |
| Carboplatin | DNA | GSTs | Yes [162] | |
| Cisplatin | DNA | CYP2E1, CYP3A4, CYP3A5, GSTs | Yes [177] | |
| Oxaliplatin | DNA | GSTs | Yes [98] | |
| Temsirolimus | mTOR | CYP3A4 | Unknown | |
| Trabectedin | DNA | CYP3A4, (CYP2C19, CYP2C9, CYP2D6, CYP2E1) | Unknown | |
The enzymes and transporters for which genetic polymorphisms are known to significantly alter the pharmacokinetics are indicated in bold
ALK anaplastic lymphoma kinase, BCR-ABL/SRc breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog/proto-oncogene tyrosine-protein kinase src, BRAF serine/threonine-protein kinase B-Raf, CD20 cluster of differentiation 20, CD30 cluster of differentiation 30, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, CYP cytochrome P450, EGFR epidermal growth factor receptor, GSTs glutathione, HER-2 human epidermal growth factor receptor 2, JAK janus kinase, mTOR mammalian target of rapamycin, multi various tyrosine kinases, PARP Poly (ADP-ribose) polymerase, PD-1 Programmed cell death protein, S-transferases, UGT uridine diphosphate glucuronosyltransferase, VEGF vascular endothelial growth factor, VEGFR 1-3 vascular endothelial growth factor subtypes 1-3