Table 10.
Importance of rare genetic variants in important pharmacokinetic genes. The frequency of functional genetic variants were calculated based on data from 130,000 individuals in the GnomAD database using a computational prediction framework specific for ADME genes (Yitian Zhou, et al., 2018).
| Class | Gene name (Gene product) | Important substrates | Estimated number of individuals that need to be screened to find one rare deleterious variant | Fraction of functional variability allotted to rare variants |
|---|---|---|---|---|
| Transporter | ABCB1 (MDR1, P-gp) | Anthracyclines, vinca alkaloids, methotrexate, etoposide, clozapine, tricyclic antidepressants, selective serotonin reuptake inhibitors, aliskiren, irinotecan, proton pump inhibitors, verapamil, zidovudine, olanzapine | 36 individuals | 28% |
| ABCC1 (MRP1) | Anthracyclines, vinca alkaloids, epipodophyllotoxins | 20 individuals | 39% | |
| ABCC3 (MRP3) | Etoposide, methotrexate | 24 individuals | 37% | |
| ABCG2 (BCRP) | Irinotecan, rosuvastatin, nitrofurantoin, leflunomide, cimetidine, glyburide, sulfasalazine | 50 individuals | 100% | |
| SLC22A1 (OCT1) | Metformin, oxaliplatin, furaminidine, acyclovir, lamivudine | 24 individuals | 3% | |
| SLCO1B1 (OATP1B1) | Statins, meglitinides, rifampicin, angiotensin II receptor antagonists | 36 individuals | 9% | |
| Phase I | CYP1A2 | Olanzapine, theophylline, clozapine, tizanidine, caffeine, flutamide, tacrine | 49 individuals | 2% |
| CYP2C9 | Warfarin, acenocoumarol, phenytoin, sulfonylureas, torasemide, fluoxetine, terbinagine, sildenafil, celecoxib, piroxicam, lesinurad, dronabinol, tolbutamide | 23 individuals | 19% | |
| CYP2C19 | Clopidogrel, tricyclic antidepressants, selective serotonin reuptake inhibitors, proton pump inhibitors, voriconazole, moclobemide. | 18 individuals | 12% | |
| CYP2D6 | Tricyclic antidepressants, selective serotonin reuptake inhibitors, codeine, tramadol, clozapine, risperidone, aripiprazole, venlafaxine, flupentixol, haloperidol, 5-HT3 receptor antagonists, tamoxifen, carvedilol, metoprolol, | 12 individuals | 7% | |
| CYP3A4 | Aripiprazole, gefitinib, erlotinib, sirolimus, cabazitaxel, dronedarone, ivabradine, ranolazine, tlithromycin, posaconazole, simvastatin, enzalutamide, protease inhibitors, ivacaftor, maraviroc, fesoterodine, phosphodiesterase type V inhibitors | 44 individuals | 27% | |
| DPYD | Fluoropyrimidines | 18 individuals | 22% | |
| Phase II | UGT1A1 | Irinotecan, lamotrigine, etoposide, belinostat, carvedilol | 22 individuals | 5% |
| TPMT | Thiopurines | 119 individuals | 6% |