Cytochrome P450 Genetic Polymorphisms Research Articles

Association between Cytochrome P450 Genetic Polymorphism and Hematological Toxicity of Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP Protocol

Association between Cytochrome P450 Genetic Polymorphism and Hematological Toxicity of Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP Protocol

Metabolism of the Tyrosine Kinase Inhibitor Masitinib In Vitro

Masitinib is an orally bioavailable inhibitor of protein kinases such as c‐kit, Lyn, Fyn and MCSFR‐1. These pathways play a key role in cell survival and proliferation of mast cells and microglia. Due to the selectivity of masitinib for these pathways, this drug is under investigation for treating neurodegenerative disorders, inflammatory disorders, as well as pancreatic and prostate cancer. Hepatotoxicity has been observed in some patients taking masitinib during clinical trials and is thought to arise from reactive metabolites formed by cytochrome P450 (CYP) enzymes in the liver. The purpose of this study was to elucidate the metabolism and bioactivation pathways of masitinib using in vitro phenotyping methods to identify the enzymes involved in masitinib metabolic activation. Masitinib (2 μM) was incubated with pooled human liver microsomes in the presence and absence of NADPH. Potassium cyanide was added to trap reactive metabolites as cyano adducts. Metabolites were analyzed using reversed‐phase liquid chromatography ‐ tandem mass spectrometry (LC‐MS/MS). To determine which enzymes are involved in forming masitinib metabolites and reactive metabolites, masitinib was incubated with human liver microsomes in the presence of P450‐selective reversible inhibitors as well as time‐dependent inhibitors. To validate the inhibitor panel findings, masitinib was also incubated with recombinant P450 enzymes. From these assays we found that the primary metabolite, N‐desmethyl masitinib, was primarily formed by CYP2C8 and CYP3A4, with contributions from CYP2D6 and CYP3A5. Other primary metabolites produced by monooxygenation of masitinib, M515a, M515b, and M515d, were formed by CYP3A4 and CYP3A5, while M515c was formed by CYP3A4 with minor contribution from CYP2D6. We also found that reactive metabolite cyano adducts MCN510 and MCN538 were formed by CYP3A4 and CYP3A5. MCN524 and MCN526 were generated by CYP3A4 with contributions from CYP2D6, CYP2C8, and CYP3A5. By elucidating these pathways, we gain further insight into the routes that generate reactive and potentially toxic metabolites of masitinib. Given the polymorphic nature of the enzymes involved, future studies are needed to determine the impact of CYP genetic polymorphisms on masitinib metabolism. This information could ultimately provide evidence to inform precision prescribing for masitinib to ensure safety and efficacy for future patients.

Association between Maternal Drug Use and Cytochrome P450 Genetic Polymorphisms and the Risk of Congenital Heart Defects in Offspring

ObjectiveThis study aimed to assess the associations between maternal drug use, cytochrome P450 (CYP450) genetic polymorphisms, and their interactions with the risk of congenital heart defects (CHDs) in offspring. MethodsA case-control study involving 569 mothers of CHD cases and 652 controls was conducted from November 2017 to January 2020. ResultsAfter adjusting for potential confounding factors, the results show that mothers who used ovulatory drugs (adjusted odds ratio [aOR] = 2.12; 95% confidence interval [CI]: 1.08–4.16), antidepressants (aOR = 2.56; 95% CI: 1.36–4.82), antiabortifacients (aOR = 1.55; 95% CI: 1.00–2.40), or traditional Chinese drugs (aOR = 1.97; 95% CI: 1.26–3.09) during pregnancy were at a significantly higher risk of CHDs in offspring. Maternal CYP450 genetic polymorphisms at rs1065852 (A/T vs. A/A: OR = 1.53, 95% CI: 1.10–2.14; T/T vs. A/A: OR = 1.57, 95% CI: 1.07–2.31) and rs16947 (G/G vs. C/C: OR = 3.41, 95% CI: 1.82–6.39) were also significantly associated with the risk of CHDs in offspring. Additionally, significant interactions were observed between the CYP450 genetic variants and drug use on the development of CHDs. ConclusionsIn those of Chinese descent, ovulatory drugs, antidepressants, antiabortifacients, and traditional Chinese medicines may be associated with the risk of CHDs in offspring. Maternal CYP450 genes may regulate the effects of maternal drug exposure on fetal heart development.

Associations and interaction effects of maternal smoking and genetic polymorphisms of cytochrome P450 genes with risk of congenital heart disease in offspring: A case-control study.

To assess associations and interactions of maternal smoking and cytochrome P450 (CYP450) genetic variants with the developments of congenital heart disease (CHD) and specific subtypes.A case–control study of 654 cases and 666 controls was conducted from November 2017 to March 2020. The exposures of interest were maternal active and passive smoking before/in the early pregnancy and CYP450 genetic polymorphisms. Data were analyzed using the Chi-square test and logistic regression analysis.After adjusting for the potential confounding factors, our study showed maternal active (ORadj = 2.34, 95%CI: 1.19–4.60) or passive (ORadj = 1.76, 95%CI: 1.34–2.31) smoking before pregnancy, passive smoking in the early pregnancy (ORadj = 3.05, 95%CI: 2.26–4.12), as well as polymorphisms of CYP450 at rs1065852 (G/A vs G/G: ORadj = 1.46, 95%CI: 1.07–1.99; A/A vs G/G: ORadj = 1.63, 95%CI: 1.15–2.33) and rs16947 (A/A vs G/G: ORadj = 3.61, 95%CI: 2.09–6.23), were significantly associated with risk of total CHD in offspring. Similar results were also found for some subtypes of CHD. Additionally, significant interactions between maternal smoking and CYP450 genes on the risk of CHD were observed.Maternal smoking and CYP450 genetic variants were associated with increased risk of CHD and specific subtypes in offspring. And the effects of CYP450 genes on CHD may be modified by maternal smoking.

The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs.

There is evidence that use of drugs with anticholinergic properties increases the risk of cognitive impairment, and increased exposure to these drugs potentiates this risk. Anticholinergic drugs are commonly used even with associated risk of adverse events. Aging, sex, and genetic polymorphisms of cytochrome P450 (CYP) enzymes are associated with alterations in pharmacokinetic processes, which increase drug exposure and may further increase the risk of adverse drug events. Due to the increasing burden of cognitive impairment in our aging population and the future of personalized medicine, the objective of this review was to provide a critical clinical perspective on age, sex, and CYP genetic polymorphisms and their role in the metabolism and exposure to anticholinergic drugs. Age‐related changes that may increase anticholinergic drug exposure include pseudocapillarization of liver sinusoidal endothelial cells, an approximate 3.5% decline in CYP content for each decade of life, and a reduction in kidney function. Sex‐related differences that may be influenced by anticholinergic drug exposure include women having delayed gastric and colonic emptying, higher gastric pH, reduced catechol‐O‐methyl transferase activity, reduced glucuronidation, and reduced renal clearance and men having larger stomachs which may affect medication absorption. The overlay of poor metabolism phenotypes for CYP2D6 and CYP2C19 may further modify anticholinergic drug exposure in a significant proportion of the population. These factors help explain findings of clinical trials that show older adults and specifically older women achieve higher plasma concentrations of anticholinergic drugs and that poor metabolizers of CYP2D6 experience increased drug exposure. Despite this knowledge neither age, sex nor CYP phenotype are routinely considered when making decisions about the use or dosing of anticholinergic medications. Future study of anticholinergic medication needs to account for age, sex and CYP polymorphisms so that we may better approach personalized medicine for optimal outcomes and avoidance of medication‐related cognitive impairment.

Trends in Tramadol: Pharmacology, Metabolism, and Misuse.

Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects. The importance of the CYP metabolism has led to the adoption of computer clinical decision support with pharmacogenomics tools guiding tramadol treatment in major medical centers. Tramadol's simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions that must be considered. Abrupt cessation of tramadol increases the risk for both opioid and serotonin-norepinephrine reuptake inhibitor withdrawal syndromes. This review provides updated important information on the pharmacology, pharmacokinetics, CYP genetic polymorphisms, drug interactions, toxicity, withdrawal, and illicit use of tramadol.

Rapid Naked-Eye Discrimination of Cytochrome P450 Genetic Polymorphism through Non-Crosslinking Aggregation of DNA-Functionalized Gold Nanoparticles.

Involvement of single‐nucleotide polymorphism (SNP) genotyping in healthcare should allow for more effective use of pharmacogenomics. However, user‐friendly assays without the requirement of a special instrument still remain unavailable. This study describes naked‐eye SNP discrimination in exon 5 of the human cytochrome P450 2C19 monooxygenase gene, CYP2C19*1 (the wild‐type allele) and CYP2C19*2 (the variant allele with G681A point mutation). The present assay is composed of allele‐specific single‐base primer extension and salt‐induced aggregation of DNA‐modified gold nanoparticles (DNA–AuNPs). Genetic samples extracted from human hair roots are subjected to this assay. The results are verified by direct sequencing. This study should promise the prospective use of DNA–AuNPs in gene diagnosis.

Rapid Naked‐Eye Discrimination of Cytochrome P450 Genetic Polymorphism through Non‐Crosslinking Aggregation of DNA‐Functionalized Gold Nanoparticles

The front cover artwork is provided by the group of Tohru Takarada at RIKEN (Japan). The image shows a colorimetric single‐nucleotide polymorphism (SNP) genotyping method that uses spontaneous aggregation of DNA‐modified gold nanoparticles (DNA–AuNPs) for the simple and rapid SNP genotyping of the human cytochrome P450 2C19 monooxygenase gene. For more details, read the full text of the Full Paper at p. 508.

Cover Picture: Rapid Naked‐Eye Discrimination of Cytochrome P450 Genetic Polymorphism through Non‐Crosslinking Aggregation of DNA‐Functionalized Gold Nanoparticles (ChemistryOpen 6/2016)

Cover Picture: Rapid Naked‐Eye Discrimination of Cytochrome P450 Genetic Polymorphism through Non‐Crosslinking Aggregation of DNA‐Functionalized Gold Nanoparticles (ChemistryOpen 6/2016)

Cytochrome P450 Genetic Polymorphism in Neonatal Drug Metabolism: Role and Practical Consequences towards a New Drug Culture in Neonatology

The cytochrome P450 superfamily (CYP450) in humans is formed by 57 functional monooxygenases critical for the metabolism of numerous endogenous and exogenous compounds. The superfamily is organized into 18 families and 44 subfamilies. CYP nomenclature is based on the identity of amino acids. The most important functions of the CYP450 are related to metabolism of endogenous compounds, detoxification of exogenous xenobiotics and decomposition of the vast majority of currently used drugs. The expression of CYP450 enzymes in the human body is characterized by a marked substrate and tissue specificity, the most important being localized in the liver, but also present in kidney, lung, brain, breast, prostate and in the small intestine. The human cytochrome P450 3A gene family (CYP3A) accounts for the largest portion of CYP450 proteins in human liver and includes 4 genes: CYP3A4, CYP3A5, CYP3A7, CYP3A43. Multiple and complex genetic variations, marked interindividual, interethnic and gender variability have been reported regarding CYP3A isoform expression and activity. Multiple factors may affect CYP3A expression and activity, such as inducers like rifampicin, phenobarbital, 3-methylcholantrene, beta-naphtoflavone, and dexamethasone. The maturation of organ systems, paralleled by ontogeny of drug-metabolizing enzymes during fetal life and in the first months of postnatal life, surely exerts profound effects on drug disposition, probably being the predominant factor accounting for age-associated changes in drug clearance. In fact, drug dosage in the perinatal period represents a continuous challenge for neonatologists. The purpose of this article is to provide a brief review of the pharmacokinetic differences between neonates and adults, showing the peculiarities of liver CYP450-related drug metabolism in the perinatal period and at birth, and to report the toxic mechanisms of liver injury in neonates, due to the most frequently utilized drugs in NICU centers.

The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation

Cytochrome P450 enzymes (CYPs) and flavin-containing monooxygenases (FMOs) likely have a role in the oxidation of intermediate metabolites of busulfan (Bu). In vitro studies to investigate the involvement of these enzymes are cumbersome because of the volatile nature of the intermediate metabolite tetrahydrothiophene (THT) and the lack of sensitive quantitation methods. This study explored the association between the CYP2C9, CYP2C19, CYP2B6 and FMO3 genotypes and sulfolane (Su, a water soluble metabolite of Bu) plasma levels in children undergoing hematopoietic stem cell transplantation (HSCT). The relationship between these genotypes and the effectiveness of myeloablative conditioning was also analyzed. Sixty-six children receiving an intravenous Bu-based myeloablative conditioning regimen were genotyped for common functional variant alleles in CYP2C9 (*2 and *3), CYP2C19 (*2 and *17), FMO3 (rs2266780, rs2266782 and rs1736557) and CYP2B6 (*5 and *9). The plasma levels of Bu and its metabolite Su were measured after the ninth Bu dose in a subset of 44 patients for whom plasma samples were available. The ratio of Bu to Su was considered the metabolic ratio (MR) and was compared across the genotype groups. Higher MRs were observed in CYP2C9*2 and *3 allele carriers (mean±s.d.: 7.8±3.6 in carriers vs 4.4±2.2 in non-carriers; P=0.003). An increased incidence of graft failure was observed among patients with an MR>5 compared with those with MR values <5 (20% vs 0%; P=0.02). In contrast, a significantly higher incidence of relapse and graft failure (evaluated as event-free survival) was observed in patients with malignant disease who carried CYP2B6 alleles with reduced function on both chromosomes compared with carriers of at least one normal allele (100% vs 40%; P=0.0001). These results suggest that CYP2C9 has a role in the oxidation reactions of THT and indicate that it may be possible to predict the efficacy of Bu-based myeloablative conditioning before HSCT on the basis of CYP genotypes and Bu MRs.

Cytochrome P450 genetic polymorphisms of Mexican indigenous populations

This review focuses on the genetic polymorphisms of the cytochrome P450 (CYP) genes in Mexican indigenous populations, who are a part of the wide ethnic diversity of this country. These native groups have a particular historical trajectory that is different from the Mexican Mestizos. This variability may be reflected in the frequency distribution of polymorphisms in the CYP genes that encode enzymes involved in the metabolism of drugs and other xenobiotics. Therefore, these polymorphisms may affect drug efficacy and safety in indigenous populations in Mexico. The present study aimed to analyze the prevalence of CYP polymorphisms in indigenous Mexicans and to compare the results with studies in Mexican Mestizos. Because the extrapolation of pharmacogenetic data from Mestizos is not applicable to the majority of indigenous groups, pharmacogenetic studies directed at indigenous populations need to be developed. The Amerindians analyzed in this study showed a low phenotypic (CYP2D6) and genotypic (CYP2D6, CYP2C9) diversity, unlike Mexican Mestizos. The frequency of polymorphisms in the CYP1A1, CYP2C19, CYP2E1, and CYP3A4 genes was more similar among the Amerindians and Mexican Mestizos, with the exception of the CYP1A2 gene, whose *1F variant frequency in Mexican Amerindians was the highest described to date.

CYP2D6 P34S Polymorphism and Outcomes of Escitalopram Treatment in Koreans with Major Depression

ObjectiveCytochrome P450 (CYP) enzymatic activity, which is influenced by CYP genetic polymorphism, is known to affect the inter-individual variation in the efficacy and tolerability of antidepressants in major depressive disorder (MDD). Escitalopram is metabolized by CYP2D6, and recent studies have reported a correlation between clinical outcomes and CYP2D6 genetic polymorphism. The purpose of this study was to determine the relationship between the CYP2D6 P34S polymorphism (C188T, rs1065852) and the efficacy of escitalopram treatment in Korean patients with MDD.MethodsA total of 94 patients diagnosed with MDD were recruited for the study and their symptoms were evaluated using the 21-item Hamilton Depression Rating scale (HAMD-21). The association between the CYP2D6 P34S polymorphism and the clinical outcomes (remission and response) was investigated after 1, 2, 4, 8, and 12 weeks of escitalopram treatment using multiple logistic regression analysis and χ2 test.ResultsThe proportion of P allele carriers (PP, PS) in remission status was greater than that of S allele homozygotes (SS) after 8 and 12 weeks of escitalopram treatment. Similarly, P allele carriers exhibited a greater treatment response after 8 and 12 weeks of escitalopram treatment than S allele homozygotes.ConclusionOur results suggest that the P allele of the CYP2D6 P34S polymorphism is a favorable factor in escitalopram treatment for MDD, and that the CYP2D6 P34S polymorphism may be a good genetic marker for predicting escitalopram treatment outcomes.

Association of cytochrome P450 genetic polymorphisms with neoadjuvant chemotherapy efficacy in breast cancer patients

BackgroundThe enzymes of the cytochrome P450 family (CYPs) play an important role in the metabolism of a great variety of anticancer agents; therefore, polymorphisms in genes encoding for metabolizing enzymes and drugs transporters can affect drug efficacy and toxicity.MethodsThe genetic polymorphisms of cytochrome P450 were studied in 395 patients with breast cancer by RLFP analysis.ResultsHere, we studied the association of functionally significant variant alleles of CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 with the clinical response to neoadjuvant chemotherapy in breast cancer patients. A significant correlation was observed between the CYP2C9*2 polymorphism and chemotherapy resistance (OR = 4.64; CI 95% = 1.01 – 20.91), as well as between CYP2C9*2 heterozygotes and chemotherapy resistance in women with nodal forms of breast cancer and a cancer hereditary load (OR = 15.50; CI 95% = 1.08 – 826.12) when the potential combined effects were examined. No significant association between chemotherapy resistance and the other examined genotypes and the potential combined clinical and tumour-related parameters were discovered.ConclusionIn conclusion, CYP2C9*2 was associated with neoadjuvant chemotherapy resistance (OR = 4.64; CI 95% = 1.01 – 20.91) in the population of interest.

Suicide cases and venlafaxine.

Piatkov I, Jones T, Van Vuuren RJ. Suicide cases and venlafaxine.Objective: Our aim was to establish whether the presence or absence of fully functioning cytochrome P450 2D6, 2C19 and 2C9 genetic alleles was associated with suicide in patients receiving venlafaxine treatment.Method: Authorisation from the NSW State Coroner to perform post-mortem genetic testing was obtained for 11 samples from deceased persons who committed suicide during treatment with venlafaxine (VENADR study).Results: All patients, but one, have at least one copy of the loss-of-function, altered or decreased cytochrome P450 enzyme activity allele. Four patients' results reveal loss-of-function genotypes, while all others were found to have diminished enzyme activity polymorphisms. Seven patients had multiple altered function polymorphisms, which included CYP2D6, CYP2C19 or CYP2C9.Conclusion: Our preliminary limited data show that neurotoxicity development, which manifests as suicide while on venlafaxine treatment, probably correlates with a higher prevalence of gene copies of altered functioning cytochrome P450 genetic polymorphisms.

Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients

Calcineurin inhibitors are necessary as immunosuppressants during hematopoietic SCT (HSCT) to prevent alloreactivity, but have unfortunate toxicities. So, we investigated the association of gene polymorphisms with the initial calcineurin inhibitor concentration and the subsequent drug dose from day 1 to day 28 among patients who underwent HSCT at a single institution. We analyzed 58 serial cases of Japanese patients receiving GVHD prophylaxis with CsA (21 cases) or tacrolimus (37 cases). We investigated eight single-nucleotide polymorphisms: rs4244285 (CYP2C19), rs15524, rs4646450, rs3800959, rs776746 (CYP3A5), rs1128503, rs2032582 and rs1045642 (MDR1). The CsA concentration was significantly higher when the genotype of CYP3A5 rs15524 was T/T (P=0.044) or rs776746 was G/G (P=0.027). The CYP3A5 rs776746 and rs4646450 genotypes were also associated with tacrolimus concentration (P=0.013 and P=0.0058, respectively). The dosage of tacrolimus was remarkably reduced from day -1 to day 28 when the patient had the CYP3A5 rs4646450 C/C and/or rs776746 G/G genotype (P=0.0010 and P=0.0021, respectively). In this study, we show that genetic variation has a predictable effect on the pharmacological responses to calcineurin inhibitors in HSCT patients.

Genotyping, Clopidogrel Metabolism, and the Search for the Therapeutic Window of Thienopyridines

It is somewhat remarkable to note that not until recently, nearly 12 years and tens of millions of treated patients after its initial approval, has the metabolism of clopidogrel, an inactive prodrug, begun to be more fully understood. Although this lack of knowledge may not be unique among common cardiovascular drugs, there are 4 characteristics of clopidogrel therapy that make this gap in understanding disconcerting: The potential for life-threatening complications (bleeding or thrombosis) at both ends of its therapeutic spectrum; the fact that 1 dose is supposed to fit all; the lack of a measureable, proven end point (such as blood pressure for antihypertensive drugs) that allows for titration to a target response; and the nearly mandatory need by many patients for clopidogrel, with no acceptable alternative until recently. Article see p 512 Historically, understanding the metabolism of a drug has been critical in identifying those patients most likely to benefit from and, more important, potentially be harmed by that drug. This is especially true for drugs with relatively narrow therapeutic windows, such as phenytoin, warfarin, and others. Although it seems safe to assume, on the basis of our extensive clinical experience, that the therapeutic window of clopidogrel is unlikely to be narrow, this certainly does not represent the depth of knowledge we would hope for after so much clinical experience and research. What we do know is that P2Y12 inhibition with thienopyridines is beneficial in preventing arterial thrombotic events, presumably requiring the achievement of some minimal level of receptor inhibition that may or may not vary on the basis of the patient and clinical scenario. We also know that it is associated with a significant increase in serious bleeding events, with higher levels of inhibition associated with greater bleeding. In the present and future practice environment, with a growing …

Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes

Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes

Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes

Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes

Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel

Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.