TABLE 4.
Important pharmacokinetic markers in preventive treatment of primary headaches.
| Drug group | Example(s) of drug(s) | SNP | Therapeutic effect | Effect on safety | Affected molecule |
|---|---|---|---|---|---|
| Antidepressants | Amitriptyline Nortriptyline | CYP2D6*4/*41, *5/*9, *4/*10 (IMs) CYP2D6*3-*4,*5, *6 (homozygous) | — | Higher risk for anticholinergic adverse effects, cardiotoxicity, dizziness Steimer et al. (2005) | Lower activity of CYP2D6 Steimer et al. (2005), Dean et al. (2012a), Hicks et al. (2013) |
| — | Amitriptyline | CYP2C19*2, *3, and *4 | — | Higher risk of adverse effects, i.e., anticholinergic adverse effects, cardiotoxicity, dizziness Steimer et al. (2005), Dean et al. (2012a) | Lower activity of CYP2C19 Goldstein et al. (1997), Aynacioglu et al., 1999) higher activity of CYP2C19 Sim et al. (2006) |
| CYP2C19*17 | |||||
| —— | TCAs | NOS3 | Better treatment response in migraine Molana et al. (2014) | — | Lower activity of NOS3 Molana et al. (2014) |
| Glu298Asp | |||||
| TT genotype | |||||
| — | Amitriptyline | “LL” genotype of HTTLPR | Better treatment response in TTH Agius and Muscat, (2019) | HTTLPR Agius and Muscat, (2019) | |
| — | Venlafaxine | CYP2D6 (IMs and PMs) | — | Gastrointestinal adverse effects such as nausea, vomiting and diarrhea Shams et al. (2006) | Lower activity of CYP2D6 Shams et al. (2006), Hicks et al. (2013) |
| HTR1B rs11568817 | Increased risk of bone complications Garfield et al. (2014), Rawson et al. (2017) | HTR1B Garfield et al. (2014), Rawson et al. (2017) | |||
| Calcium channel blockers | Verapamil | PLCE1 rs10882386 | Higher effect in migraine Lopez et al. (2001), Smrcka et al. (2012), Cutrer et al. (2021) | — | PLC Lopez et al. (2001), Smrcka et al. (2012) |
| — | — | ITGAL rs2230433 | Higher effect in migraine Cutrer et al. (2021) | — | Integrin alpha L chain of a heterodimeric integral membrane receptor protein Cutrer et al. (2021) |
| — | — | EHBP1L1 rs6591182 | Higher effect in migraine Cutrer et al. (2021) | — | — |
| — | — | STRIP2 rs676947 | — | — | — |
| SRP72 rs144645569 | |||||
| — | — | CACNA1C 527974G > A rs2239050 CACNA1D rs312481G > A rs3774426C > T CACNB2 rs2357928 | — | Higher risk of cardiovascular outcomes Bremer et al. (2006), Kamide et al. (2009), Niu et al. (2010) | Voltage-gated calcium channel (VGCC) Bremer et al. (2006), Kamide et al. (2009), Niu et al. (2010) |
| ARBs | Candesartan | LRP1 rs11172113 | Lower effect in migraine (trend) Christensen et al. (2016) | — | LRP1 Christensen et al. (2016) |
| — | — | rs12134493 | Higher effect in migraine (trend) Christensen et al. (2016) | — | — |
| near TSPAN2 | |||||
| — | — | rs6790925 near TGFBR2 | Higher effect in migraine (trend) Christensen et al. (2016) | — | — |
| — | — | rs10504861 near MMP16 | Higher effect in migraine (trend) Christensen et al. (2016) | — | — |
| Anticonvulsants | Topiramate | MDR1 C3435T | Risk factor for treatment failure in migraine Atasayar et al. (2016) | — | MDR1 Atasayar et al. (2016) |
| — | Valproate sodium | rs10504861 near MMP16 | Higher effect in migraine Christensen et al. (2016) | — | MMP16 Christensen et al. (2016) |
| — | — | PRDM16 rs2651899 | Lower effects in migraine without aura Christensen et al. (2016) | Higher risk of hepatotoxicity Zhao et al. (2017) | PRDM16 Christensen et al. (2016) |
| CYP2C9*3, CYP2A6*1/*4, CYP2A6*4/*4 | CYP2C9, CYP2A6 Zhao et al. (2017) | ||||
| CYP2C19*2, CYP2C19*3 | Higher risk of weight gain Noai et al. (2016) | CYP2C19 Noai et al. (2016) | |||
| UGT1A6 19T > G, 552A > C, 541A > G | Ataxia, liver damage, metabolic changes, tremor, hallucinations, pancreatitis, and weight gain Goey et al. (2016) | Increased UGT enzyme activity Goey et al. (2016) | |||
| — | Phenytoin | CYP2C9*2 | — | Higher likelihood skin and neurological adverse effects, hirsutism, teratogenesis (Mamiya et al., 1998, Ninomiya et al. (2000), Kidd et al. (2001), Ramasamy et al. (2007), Depondt et al. (2011), Babu et al. (2013), Dorado et al. (2013) | CYP2C9 |
| CYP2C9*3 | — | ||||
| CYP2C19*2 | CYP2C19 | ||||
| CYP2C19*3 | — | ||||
| CYP2C19*4 | — | ||||
| — | — | EPHX1 113H 139R | — | Teratogenesis, congenital craniofacial anomalies Dennery (2007) Azzato et al. (2010), Depondt et al. (2011), cutaneous adverse drug reactions: Stevens–Johnson syndrome and toxic epidermal necrolysis, hematologic and hepatic toxicity Karnes et al. (2021) | EPHX1 |
| HLA-B*15:02 | HLA Karnes et al. (2021) | ||||
| — | Carbamazepine Valproate sodium | GSTM1*0/*0 | — | Carbamazepine and Valproate sodium induced hepatotoxicity Ueda et al. (2007), Fukushima et al. (2008), Chbili et al. (2018) | GSTM1 Bu et al. (2005) |
| — | — | ABCC2 c. 1249 G > A | — | Carbamazepine and Valproate sodium neurologic adverse effects Kim et al. (2010b) | MRP2,Kim et al. (2010b) |
| — | Carbamazepine | HLA-B*15:02, A*31:01, B*15:11,-A*02:01 B*57:01,-B*58:01 | — | Higher risk for cutaneous adverse effects Hung et al. (2006), Man et al., 20072008, Ikeda et al. (2010), Kaniwa et al. (2010), McCormack et al. (2011) | HLA |
| EPHX1 C allele, C-G diplotype of 337T > C | Stevens-Johnson syndrome and toxic epidermal necrolysis He et al. (2014) | EPHX1 He et al. (2014) | |||
| CYP3A5*3/*3 | CBZ toxicity Al-Gahtany et al. (2014) | CYP3A5 Al-Gahtany et al. (2014) | |||
| CYP2C19*2 CYP2C19*3 | Stevens-Johnson syndrome and toxic epidermal necrolysis Laska et al. (2017) | CYP2C19 Laska et al. (2017) | |||
| Neurotransmitter release antagonists | Onabotulinum toxinA | TRPV1 rs222749 allele A | Higher effect in migraine Moreno-Mayordomo et al. (2019) | — | TRP Moreno-Mayordomo et al. (2019) |
| — | — | CALCA rs3781719 allele C | — | — | CGRP Moreno-Mayordomo et al. (2019) |
CYP450: Cytochrome P; TCAs: Tricyclic antidepressants; HTTLPR: serotonin transporter gene-linked polymorphic region; 5-HT: 5-hydroxytryptamine; LRP1: lipoprotein receptor-related protein 1; MMP16: matrix metalloproteinase-16; UGT: Uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase); EPHX1: Microsomal epoxide hydrolase; HLA: Human leukocyte antigen; GSTM1: Glutathione S-transferase class M1; TTH: Tension-type headache.