Table 1. Polymorphic CYP substrates within the ISS drug list: Information about involvement of polymorphic drug metabolism from the drug labels or from evidence-based pharmacogenetic guidelines.
Among the drugs listed in the ISS repository, specific warnings related to pharmacokinetic effects have been identified in the label section of 14 drugs. For six drugs on the list, specific therapy modifications (alternative drugs) or dosing adjustments are proposed in existing evidence-based guidelines.
| CYP2D6 substrates on ISS drug list | Indication | Information about polymorphic enzymes in the drug label | Dosing Guidelines: CPIC/ GWPG | References | Level of evidence* |
|---|---|---|---|---|---|
| Metoprolol | Heart failure, hypertension | FDA: warnings about pharmacogenetics and drug interactions | PM: 75% UM: up to 250% | [10, 11] | 3 |
| Diphenhydramine | Vomiting, allergic rhinitis | Warning about drug interactions with drugs metabolized by CYP2D6 | [12] | 3 | |
| Cetirizine | Vomiting, allergic rhinitis | Information about drug metabolism via CYP2D6 | [13] | 1 | |
| Loratadine | Vomiting, allergic rhinitis, urticaria | Information about drug metabolism via CYP2D6 | [14] | 1 | |
| Meclizine | Vomiting, allergic rhinitis | Information about drug metabolism via CYP2D6 | [15] | 1 | |
| Ondansetron | vomiting | Information about drug metabolism via CYP2D6 | [16] | 3 | |
| Promethazine | Rhinitis, urticarial, Sedation, vomiting | Information about drug metabolism via CYP2D6 | [17] | 3 | |
| Tamsulosin | Prostate hyperplasia | Information about drug metabolism, high exposure in PM as compared to EM | [18] | 2 | |
| Acetaminophen | Pain, fever | Warning about interaction potential with CYP2D6 substrates | [19] | 1 | |
| Hydrocodone | Pain | CYP2D6 involved in activation; PMs less efficacy | [20] | 1 | |
| Venlafaxine | Depression | Metabolism of venlafaxine to the active metabolite, total active moiety not affected by polymorphism | 80% in PMs 170% in UMs or select an alternative drug, Cardiotoxic risk higher in PMs | [21, 22] | 3 |
| Aripiprazole | Psychosis | Dose recommendations in FDA label, and interaction warning | Reduce dose in PMs to 67% UMs no recommendation | [23] | 2 |
| CYP2C19 substrates | |||||
| Diazepam | Sleep disturbances | Information about drug metabolism and interaction via CYP2C19 | [24] | 2 | |
| Sertraline | Depression | Information about drug metabolism via CYP2C19 | Reduce PM dose to 50% UMs no recommendation | [6] | 2 |
| Omeprazole | Reflux | Drug interactions | UM dose 100–200% increased | [25] | 3 |
| CYP2C9 substrates | |||||
| Ibuprofen | Pain, Fever | CYP2C9 and CYP2C8 involved in metabolism | CYP2C8 and 9 combined genotype involved in GI bleeding side effects | [26] | 3 |
| Phenytoin | Epilepsia, seizures | PMs: enhanced risk of toxicity | PMs: 50%, higher risk for skin toxicity; IMs: 75% of dose | [27] | 3 |
| Ketamine | Anesthesia, pain | Minor enzyme involved in metabolism | [28] | 1 | |
| Acetylsalicylic acid | Pain, fever, cardiovascular | Minor enzyme, Drug interactions | CYP2C9 PM higher risk for urticaria | [29] | 1 |
| Sulfamethoxazole | Antibiotic | Information about m via CYP2C9 | Risk of hemolysis in Glucose 6 phosphatase dehydrogenase deficiency | [30] | 1 |
| Loperamide | Diarrhea | Interaction warning | [31] | 1 | |
| CYP1A2 | |||||
| Melatonin | Daytime sleep, insomnia | Metabolism, Interactions | [32] | 3 | |
| Caffeine | Sleepiness | Metabolism, Interactions | [33] | 3 | |
| Lidocaine | Anaesthetic | Interactions | [34] | 3 |
* Level of evidence: 1: in vitro data only, 2: in vivo pk data, 3: clinical data on efficacy and/or side effects