Applications of CYP450 Testing in the Clinical Setting

Abstract

Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25 % of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homoz...

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…Examples of therapeutic drugs for which phenotyping using alternative strategies may be applied are the CYP2D6 substrates imipramine, nortriptyline (tricyclic antidepressants), haloperidol, risperidone (antipsychotics), codeine and tramadol (opioid analgesics), the CYP2C19 substrates omeprazole, lansoprazole (proton-pump inhibitors) and clopidogrel (platelet aggregation inhibitor), the CYP1A2 substrates clozapine and olanzapine (antipsychotics) and the CYP2C9 substrate warfarin (anticoagulant) [3,6,8]. For several of these, it remains to be fully established if and to what extent phenotyping (and resulting dose adaptation) indeed results in a better clinical outcome.…”

“…Likewise, when metabolization results in inactivation of a parent drug, higher than normal enzyme activity may cause standard drug therapy to fail. In these cases, increasing the drug dose is needed to obtain the same level of efficacy [3,6].…”

“…Some CYP450 enzymes, in particular CYP2D6, CYP2C19 and CYP2C9, are encoded by highly polymorphic genes and distinct subpopulations can be identified based on the genetic signature [4,7,8]. For many drugs metabolized by these enzymes, clinical outcome could be correlated with a certain genotype and genotyping a patient has proven to be a reliable strategy to assess the metabolic phenotype [3,6,8]. This approach holds the advantages that is has to be performed only once for each individual and that intake of test drugs is not required.…”

Does CYP2D6 Genotyping have a Role in Guiding Tamoxifen Therapy?

“…The pro-drug, tamoxifen, is extensively metabolised by CYP2D6 into therapeutically-active moieties, 4-hydroxytamoxifen and endoxifen; their affinity for the oestrogenreceptors is ~100-fold greater than tamoxifen and their antioestrogenic potency in suppressing ER-dependent cell proliferation is 30-100-fold stronger than tamoxifen [6,9,[11][12][13][14][15].…”

“…Tamoxifen decreases the risk of relapse by half and the mortality rate by nearly a third in patients with ER (+) breast cancer which count for approximately 80% of all breast cancers [1][2][3]. While aromatase inhibitors are more effective for treating post-menopausal patients with ER (+) breast cancer, tamoxifen was approved by the FDA for metastatic breast cancer and as an alternative to aromatase inhibitors for the chemoprevention in post-menopausal women [4][5][6]. Hence, tamoxifen remains the gold standard for ER (+) breast cancer.…”