Table 27.1.
Pharmacogenomic Profile of Antidementia Drugs
| Donepezil | |
|---|---|
| Category | Antidementia agent/cholinesterase inhibitor |
| Mechanism | Centrally active, reversible acetylcholinesterase inhibitor; increases acetylcholine available for synaptic transmission in CNS |
| Genes | |
| Pathogenic | APOE, CHAT |
| Mechanistic | CHAT, ACHE, BCHE |
| Metabolism: substrate | CYP2D6 (major), CYP3A4 (major), UGTs, ACHE |
| Metabolism: inhibitor | ACHE, BCHE |
| Transporter | ABCB1 |
| Galantamine | |
| Category | Antidementia agent/cholinesterase inhibitor |
| Mechanism | Reversible and competitive acetylcholinesterase inhibition leading to increased concentration of acetylcholine at cholinergic synapses; modulates nicotinic acetylcholine receptor; may increase glutamate and serotonin levels |
| Genes | |
| Mechanistic | APOE, APP |
| Pathogenic | ACHE, BCHE, CHRNA4, CHRNA7, CHRNB2 |
| Metabolism: substrate | CYP2D6 (major), CYP3A4 (major), UGT1A1 |
| Metabolism: inhibitor | ACHE, BCHE |
| Memantine | |
| Category | Antidementia Drug; N-methyl-d-aspartate Receptor Antagonist |
| Mechanism | Binds preferentially to NMDA receptor-operated cation channels; may act by blocking glutamate actions, mediated in part by NMDA receptors. Antagonists: GRIN2A, GRIN2B, GRIN3A, HTR3A, CHRFAM7A |
| Genes | |
| Pathogenic | APOE, PSEN1, MAPT |
| Mechanistic | GRIN2A, GRIN2B, GRIN3A, HTR3A, CHRFAM7A |
| Metabolism: inhibitor | CYP1A2 (weak), CYP2A6 (weak), CYP2B6 (strong), CYP2C9 (weak), CYP2C19 (weak), CYP2D6 (strong), CYP2E1 (weak), CYP3A4 (weak) |
| Pleiotropic | APOE, MAPT, MT-TK, PSEN1 |
| Rivastigmine | |
| Category | Antidementia Agent/Cholinesterase Inhibitor |
| Mechanism | Increases acetylcholine in CNS through reversible inhibition of its hydrolysis by cholinesterase |
| Genes | |
| Pathogenic | APOE, APP, CHAT |
| Mechanistic | ACHE, BCHE, CHAT, CHRNA4, CHRNB2 |
| Metabolism: inhibitor | ACHE, BCHE |
| Pleiotropic | APOE, MAPT |
| Tacrine | |
| Category | Antidementia agent/cholinesterase inhibitor |
| Mechanism | Elevates acetylcholine in cerebral cortex by slowing degradation of acetylcholine |
| Genes | |
| Pathogenic | APOE |
| Mechanistic | ACHE, BCHE, CHRNA4, CHRNB2 |
| Metabolism: substrate | CYP1A2 (major), CYP2D6 (minor), CYP3A4 (major) |
| Metabolism: inhibitor | ACHE, BCHE, CYP1A2 (weak) |
| Transporter | SCN1A |
| Pleiotropic | APOE, MTHFR, CES1, LEPR, GSTM1, GSTT1 |
Source: Cacabelos [113].