Cyp2d6 Information and Courses from MediaLab, Inc.
These are the MediaLab courses that cover Cyp2d6 and links to relevant pages within the course.
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| CYP450s Many CYP450 enzymes have been characterized, and the substrates (drugs) that each can recognize have been worked out to a large extent. These subfamilies of CYP450 enzymes have all been associated with polymorphisms that can affect drug disposition: CYP1A2, CYP2C9, CYP2C19 and CYP2D6. | View Page |
| Enzyme Abnormalities and Drugs The following is a list of enzymes for which known mutations have been associated with clinical effects. Enzymes Substrates (Drugs) Acetylaldehyde dehydrogenase Alcohol Acetylcholinesterase Succinylcholine Alcohol dehydrogenase Alcohol Dihydropyrimidine dehydrogenase Fluorouracil CYP2C9 Warfarin, phenytoin, losartan CYP2C19 Diazepam, omeprazole (Prilosec) CYP2D6 Many antidepressants, opioids, antiarrhythmics Glucose-6-phosphate dehydrogenase Aspirin, quinidine N-acetyltransferase Procainamide, isoniazid Thioprine methyltransferase 6-mercaptopurine UDP-glucuronosyl transferase Acetaminophen, tolbutamide, irinotecan | View Page |
| Clinical Utility The ultimate goal in measuring CYP450 function or identifying polymorphisms is to predict effective therapeutic doses and responses in patients.Polymorphisms are identified using molecular techniques (allele-specific PCR, restriction digests, sequencing, hybridization assays, bead-based systems, microarrays, pyrosequencing, et al).Although most clinical labs do not offer PGx testing, reference labs are beginning to market these tests. For example, one reference laboratory in the Midwest that offers CYP2D6 profiling measures about one dozen of the most common and significant mutation sites on this enzyme. This allows for detection of approximately 98% of the known CYP2D6 polymorphisms. The laboratory then generates a report which will advise the physician on the patient's drug-metabolizing status.Estimates show that 6-10% of the general population have a complete deficiency of CYP2D6, with the prevalence of mutations varying from <1% to as much as 21% within a given population. | View Page |
| CYP450 Induction and Inhibition Variables other than mutations also affect CYP450 enzymes. Many drugs are able to induce CYP450 enzymes, and CYP450s can be inhibited by a variety of substances. For example, CYP2D6 can be inhibited by the common medications cimetidine (Tagamet) and fluoxetine (Prozac). Since many patients are on multiple medications and since dietary and environmental factors can change, CYP450 expression levels cannot be solely predicted based on their genotype. Some CYP450 inducers and inhibitors are listed in the table on the following page. | View Page |
| A patient is taking cimetidine for a stomach ulcer. This drug inhibits CYP2D6. The patient is now prescribed amphetamine for narcolepsy. Amphetamine is metabolized by CYP2D6. What would you predict? | View Page |
| CYP2D6 CYP2D6 has received the most attention: It is estimated that about 25% of common drugs are metabolized by CYP2D6. CYP2D6 accounts for only about 1% of all CYP450 enzymes, but it is important in the metabolism of about 100 drugs. There are more than 80 genetic variants that have been described in the CYP2D6 gene. The normal, wild-type allele displays normal metabolic activity whereas some of the variant forms have enhanced or diminished activity. The variants can be grouped generally according to the resulting alterations in protein function. The groupings correlate with four major enzyme metabolic capacities (phenotypes): poor, intermediate, extensive (normal), or ultra-rapid metabolizers. | View Page |
| CYP450 Induction and Inhibition CYP450 Inhibitor Inducer CYP1A2 Amiodarone Cimetidine Ciprofloxacin Tobacco CYP2C9 Amiodarone Fluvastatin Isoniazid Fluconazole Rifampin Secobarbital CYP2C19 Cimetidine Indomethacin Ketokonazole Prednisone CYP2D6 Celecoxib Cimetidine Cocaine Methadone Pentazocine Imipramine Desipramine Amitriptyline CYP2E1 Disulfiram Fluoxetine Ethanol Isoniazid CYP3A Midazolam Erythromycin Methadone Phenobarbital Dexamethasone Note: This is not an exhaustive listing of inducers and inhibitors.Reference: Tanaka E, Terada M, Misawa S. Cytochrome P450 2E1: it's clinical and toxicological role. J Clin Pharm Ther. 2000 Jun;25(3):165-75. | View Page |
| Genotype versus Phenotype Phenotyping involves measuring the metabolism of a probe drug. For example, with CYP2D6, dextromethorphan or debrisoquine can be given to a patient to see how well the drug is metabolized. Both these drugs are safe and extensively metabolized by CYP2D6. By measuring the parent drug and the metabolite in urine, the metabolic capacity of a CYP450 enzyme can be estimated. Such testing is complex and tedious, however, and has not become routine in clinical laboratories. Therefore, genotyping is likely to be the main tool that is used for assessing the PGx of a patient. | View Page |