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Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis.
Danese, E, Montagnana, M, Johnson, JA, Rettie, AE, Zambon, CF, Lubitz, SA, Suarez-Kurtz, G, Cavallari, LH, Zhao, L, Huang, M, et al
Clinical pharmacology and therapeutics. 2012;(6):746-56
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Abstract
A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I(2) = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
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Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis.
Liang, R, Wang, C, Zhao, H, Huang, J, Hu, D, Sun, Y
Thrombosis research. 2012;(1):38-44
Abstract
INTRODUCTION Warfarin is a commonly used oral anticoagulant and the dosage is individually adjusted on the basis of the international normalized ratio (INR) monitoring. It is well known that gene polymorphisms of CytochromeP450 (CYP) 2C9 gene and the vitamin K epoxide reductase complex 1 (VKORC1) were significantly associated with warfarin dose. However, the association between Cytochrome P450 4F2 (CYP4F2) polymorphism and warfarin dose requirement is still controversial. This study was to investigate the influence of the CYP4F2 polymorphism, V433M (rs2108622) on warfarin dose for patients by meta-analysis. METHODS Strict inclusion and exclusion criteria were set, and the studies prior to December 19, 2010 were searched in PubMed, EMBASE and CNKI. References were examined and experts of primary studies were consulted for additional information. Revman 5.0.2 software was used to analyze the relationship between warfarin maintenance dose and CYP4F2 polymorphism RESULTS Thirteen studies were included in the meta-analysis which consisted of Caucasian, Asian and African populations. Compared to individuals with the homozygous CYP4F2 genotype (CC), carriers of CT, TT genotypes required 10.0% (95% confidence interval(CI) 4.0-15.0) and 21.0% (95% CI 9.0-33.0) higher warfarin doses respectively (P value <0.05). In addition, T carriers required 11.0% (95% CI 6.0-17.0) higher warfarin dose than CC genotype. CONCLUSIONS Our study showed that polymorphism of CYP4F2 had a moderate but statistically significant association with the variation of interindividual warfarin dose. However, whether CYP4F2 can improve the prediction of warfarin dose warrants need further investigation when combined with environmental factors.
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No association between CYP1B1 Val432Leu polymorphism and breast cancer risk: a meta-analysis involving 40,303 subjects.
Yao, L, Fang, F, Wu, Q, Zhong, Y, Yu, L
Breast cancer research and treatment. 2010;(1):237-42
Abstract
Breast cancer is the most common cancer in women. To date, many publications have evaluated the association between Cytochrome P450 1B1 (CYP1B1) Val432Leu polymorphism and breast cancer risk. However, the results remain inconclusive. In order to derive a more precise estimation of the association, a meta-analysis was performed in this study. By searching Medline, Pubmed, and ISI Web of Knowledge databases, 26 studies including 19,028 cases and 21,275 controls were collected for CYP1B1 Val432Leu polymorphism. Crude ORs with 95% CIs were used to assess the strength of association between CYP1B1 Val432Leu polymorphism and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Overall, no significant associations between CYP1B1 Val432Leu polymorphism and breast cancer susceptibility were found for Val/Val versus Leu/Leu (OR = 0.98; 95% CI: 0.90-1.06), Val/Leu versus Leu/Leu (OR = 1.01; 95% CI: 0.93-1.09), Val/Val + Val/Leu versus Leu/Leu (OR = 1.00; 95% CI: 0.93-1.08) and Val/Val versus Val/Leu + Leu/Leu (OR = 0.96; 95% CI: 0.91-1.01). In the stratified analysis by ethnicity, menopausal status and sources of controls, significant associations were still not observed in all genetic models. In conclusion, this meta-analysis provides strong evidence that CYP1B1 Val432Leu polymorphism is not associated with breast cancer risk.
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Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects.
Darwish, M, Kirby, M, Robertson, P, Hellriegel, ET
Clinical pharmacokinetics. 2008;(1):61-74
Abstract
BACKGROUND AND OBJECTIVE Armodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYP1A2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate. METHODS Healthy men and nonpregnant women aged 18-45 years with a body mass index of ≤30 kg/m(2) each participated in one of three open-label studies. Studies 1 and 2 were sequential design studies in which caffeine (oral 200 mg) or midazolam (2 mg intravenously followed by 5 mg orally) was administered before initiation of oral armodafinil administration and again after at least 22 days of oral armodafinil administration at 250 mg/day. Study 3 was a two-way crossover study in CYP2C19 extensive metabolizers to whom omeprazole (oral 40 mg) was administered alone or with oral administration of armodafinil 400 mg 2 hours before the omeprazole dose. Pharmacokinetic samples were obtained for caffeine, midazolam and omeprazole for up to 48 hours postdose. The primary pharmacokinetic parameters included the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum observed drug plasma concentration (C(max)). Safety and tolerability were also assessed. RESULTS A total of 77 healthy subjects participated in the three studies (study 1, n = 29; study 2, n = 24; study 3, n = 24). Prolonged armodafinil administration had no effect on the C(max) or the AUC of oral caffeine compared with administration of caffeine alone. However, prolonged administration of armodafinil reduced the AUC of midazolam after intravenous and oral doses by approximately 17% and 32%, respectively, and decreased the C(max) of oral midazolam by approximately 19% compared with administration of midazolam alone. Armodafinil coadministration increased the AUC of oral omeprazole by approximately 38% compared with administration of omeprazole alone. Armodafinil alone or in combination with each of the three probe substrates was well tolerated, with headache and dizziness being the most commonly reported adverse events. CONCLUSIONS Armodafinil did not induce CYP1A2 but was a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 in healthy subjects. Armodafinil was generally well tolerated when administered with caffeine, midazolam or omeprazole. Dosage adjustments may be required for drugs that are substrates of CYP3A4 (e.g. ciclosporin, triazolam) and CYP2C19 enzymes (e.g. diazepam, phenytoin) when administered with armodafinil.
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Pharmacogenomic effect of cytochrome P450 2C9 polymorphisms in different populations.
Wiwanitkit, V
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2006;(2):219-22
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Abstract
Presently, warfarin sodium or coumadin is the therapeutic drug of choice for maintenance anticoagualtion therapy. One of several factors underlying the variability in warfarin dose response in the patients receiving this oral anticoagulant is a genetic predisposition, especially the CYP2C9 polymorphisms. The pharmacogenomic effect of CYP2C9 polymorphisms is assessed in different racial populations. A retrospective review was performed with an electronic search engine on this topic to get the data for further meta-analysis. A significant correlation between population ethnicity and gene frequencies was detected in this study. A significant low frequency of CYP2C9 variants among the Asian can be demonstrated. The clinical correlation between CYP2C9 polymorphism and warfarin metabolism was also assessed. Four available case-control reports were selected for this meta-analysis. CYP2C9 variants are strongly associated with low-dose warfarin requirement. In summary, the CYP2C9 variants strongly affect the warfarin dose requirement. This phenomenon is ethnically dependent. Due to the high variant frequency among whites in the West, the investigation for CYP2C9 might be useful for this population, not the Asians, whose variant frequency is very low.