Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin

Kim, Myong Jin; Nafziger, Anne N.; Kashuba, Angela D. M.; Kirchheiner, Julia; Bauer, Steffen; Gaedigk, Andrea; Bertino, Joseph S.

doi:10.1007/s00228-006-0124-0

Cited by 17 publications

(14 citation statements)

References 19 publications

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“…In bronchial biopsies of smokers, CYP2C9 is significantly induced compared to non-smokers (Thum et al, 2006). However, the effect of smoking on CYP2C9 enzyme activity is inconsistent (Kim et al, 2006;Llerena et al, 2014). Although age and body weight were significant predictors of CYP2C9 enzyme activity in a univariate analysis, the contribution of these variables did not reach significance in the multivariate analysis.…”

Section: Discussionmentioning

confidence: 90%

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

Hatta

Lundblad

Ramsjö

et al. 2015

OMICS: A Journal of Integrative Biology

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Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p<0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.

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Section: Discussionmentioning

confidence: 90%

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

Hatta

Lundblad

Ramsjö

et al. 2015

OMICS: A Journal of Integrative Biology

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“…There is a marked within-and between-individual variability in warfarin dose requirements and different factors associated with patient response to warfarin treatment, which makes the monitoring of warfarin therapy more difficult [13][14][15][16][17][18][19]. With regard to the ethnic differences among patients, it has been shown that Asian populations require a markedly lower warfarin maintenance dose than Caucasians and African-Americans; however, the mechanisms underlying these differences still remain elusive [20,21].…”

Section: Introductionmentioning

confidence: 99%

Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application

Kwon

Kim

et al. 2009

Ann Lab Med

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, 건양대학교 의과대학 진단검사의학교실 5 515 515Background : Warfarin is a widely used oral anticoagulant with broad within-and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice.Methods : We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations.Results : The mean maintenance dose of warfarin in 105 patients was 4.1±1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3±0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r 2 =0.259, P<0.001) was higher than that with INR (r 2 =0.029, P=0.072). Conclusions : There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment. (Korean J Lab Med 2009;29:515-23)

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“…To date, the effect of smoking on the first TTA time remains uncertain. A prior study (37) have demonstrated that the drug distribution volume, steady-state level and half-life of warfarin were increased by 11, 13 and 23% following smoking cessation, whereas the clearance rate decreased by 13%. Other studies (38,39) have suggested that the use of warfarin in smokers is associated with an increased INR following smoking cessation.…”

Section: ------------------------------------------------------------mentioning

confidence: 97%

Analysis of the first therapeutic-target-achieving time of warfarin therapy and associated factors in patients with pulmonary embolism

Gong

Wang

Yuan

2016

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to investigate the factors affecting the first therapeutic-target-achieving (TTA) time of warfarin therapy in patients with acute pulmonary embolism (PTE). Between January 2008 and June 2013, patients with PTE confirmed by transpulmonary arterial enhanced computed tomographic pulmonary angiography or pulmonary ventilation perfusion scanning were included in the present study. Data collected included demographic information, history of tobacco and alcohol intake, basic diseases (stable and unstable hypertension, diabetes, heart failure, cancer/cerebral infarction, old myocardial infarction and atrial fibrillation), liver and kidney function, the haemoglobin and platelet count of the blood, international normalized ratio monitoring, warfarin dosage adjustment and medication combinations. Dynamic changes in international normalized ratio, anticoagulant efficacy, and adverse events within 90 days were monitored and analyzed. Univariate analysis demonstrated that the following factors affect the first TTA time: Initial dose, body mass index (BMI), liver function, heart failure, and the administration of levofloxacin, cephalosporins, and blood circulation-activating drugs. Logistic regression analysis revealed that the following were independent factors of the first TTA time: Initial dose, BMI, liver function, heart failure and levofloxacin. Therefore, the results of the present study demonstrated that various factors may affect the first TTA time of warfarin therapy, including the initial dose, BMI, liver function, heart function and concomitant medication.

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Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin

Abstract: Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers.

Cited by 17 publications

References 19 publications

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application

Analysis of the first therapeutic-target-achieving time of warfarin therapy and associated factors in patients with pulmonary embolism

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