Silvana Borges

Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States

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Publications (9)34.87 Total impact

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    ABSTRACT: Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. The overall performance of the 3 gene scoring systems without consideration of CYP2D6-inhibiting medications in predicting CYP2D6 phenotype was poor in both the training set (R(2) = 0.24, 0.22, and 0.18) and the validation set (R(2) = 0.30, 0.24, and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R(2) values in the training and validation data sets were nearly twice as high as the genotype-only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41), respectively. The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 activity score doubled the ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, as yet unidentified factors must be involved in tamoxifen activation.
    The Journal of Clinical Pharmacology 04/2010; 50(4):450-8. · 2.84 Impact Factor
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    ABSTRACT: A mixture normal model has been developed to partition genotypes in predicting quantitative phenotypes. Its estimation and inference are performed through an EM algorithm. This approach can conduct simultaneous genotype clustering and hypothesis testing. It is a valuable method for predicting the distribution of quantitative phenotypes among multi-locus genotypes across genes or within a gene. This mixture model's performance is evaluated in data analyses for two pharmacogenetics studies. In one example, thirty five CYP2D6 genotypes were partitioned into three groups to predict pharmacokinetics of a breast cancer drug, Tamoxifen, a CYP2D6 substrate (p-value = 0.04). In a second example, seventeen CYP2B6 genotypes were categorized into three clusters to predict CYP2B6 protein expression (p-value = 0.002). The biological validities of both partitions are examined using established function of CYP2D6 and CYP2B6 alleles. In both examples, we observed genotypes clustered in the same group to have high functional similarities. The power and recovery rate of the true partition for the mixture model approach are investigated in statistical simulation studies, where it outperforms another published method.
    Cancer informatics 01/2010; 9:93-103.
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    ABSTRACT: N-Desmethyltamoxifen (NDM), a major primary metabolite of tamoxifen, is hydroxylated by cytochrome P450 (CYP) 2D6 to yield endoxifen. Because of its high antiestrogenic potency, endoxifen may play an important role in the clinical activity of tamoxifen. We conducted a prospective trial in 158 patients with breast cancer who were taking tamoxifen to further understand the effect of CYP2D6 genotype and concomitant medications on endoxifen plasma concentrations. Medication history, genotype for 33 CYP2D6 alleles, and plasma concentrations of tamoxifen and its metabolites were determined at the fourth month of tamoxifen treatment. By use of a mixture model approach, endoxifen plasma concentration identified 2 phenotypic groups, whereas 4 were defined by the endoxifen/NDM plasma concentration ratio. Three distinct genotype groups were identified in the distribution of endoxifen/NDM ratio: (1) low ratios composed of patients lacking any functional allele (mean, 0.04 +/- 0.02); (2) intermediate ratios represented by patients with 1 active allele (mean, 0.08 +/- 0.04); and (3) high ratios composed of patients with 2 or more functional alleles (mean, 0.15 +/- 0.09). Endoxifen/NDM plasma ratios were significantly different between these groups (P < .001). The mean endoxifen plasma concentration was significantly lower in CYP2D6 extensive metabolizers who were taking potent CYP2D6 inhibitors than in those who were not taking CYP2D6 inhibitors (23.5 +/- 9.5 nmol/L versus 84.1 +/- 39.4 nmol/L, P < .001). CYP2D6 genotype and concomitant potent CYP2D6 inhibitors are highly associated with endoxifen plasma concentration and may have an impact on the response to tamoxifen therapy. These iterative approaches may be valuable in the study of other complex genotype-phenotype relationships.
    Clinical Pharmacology &#38 Therapeutics 08/2006; 80(1):61-74. · 6.85 Impact Factor
  • Journal of Psychiatric Practice 08/2006; 12(4):244-9. · 1.29 Impact Factor
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    Article: PI-24
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    ABSTRACT: Background/aims: Tamoxifen is widely used for the treatment and prevention of breast cancer. Endoxifen, one of its secondary metabolites, is formed by the genetically polymorphic CYP2D6 enzyme. Due to its high antiestrogenic potency, it may play an important role in the efficacy of tamoxifen. We conducted a prospective trial in 158 women with breast cancer to further understand the effect of CYP2D6 on the formation of endoxifen.Methods: Medication history and plasma concentrations of tamoxifen and its metabolites were determined at the fourth month of tamoxifen treatment. We also genotyped for 29 CYP2D6 alleles.Results: Mean endoxifen plasma concentration was significantly lower in CYP2D6 extensive metabolizers who were on CYP2D6 inhibitors than in those who were not on CYP2D6 inhibitors (39.5 vs. 71.5 nM, p < 0.01). This decrease was more pronounced with potent inhibitors of CYP2D6 such as paroxetine and fluoxetine than with weak CYP2D6 inhibitors (e.g. sertraline and citalopram). In fact, mean endoxifen plasma concentration in patients taking potent inhibitors was comparable to that in CYP2D6 poor metabolizers. Concomitant treatment with venlafaxine did not show any significant effect on mean endoxifen plasma concentration. Tamoxifen and its other metabolites were not affected by concurrent use of CYP2D6 inhibitors.Conclusions: Potent CYP2D6 inhibitors markedly reduce endoxifen plasma concentration, and may have a negative impact on the response to tamoxifen therapy.
    Clinical Pharmacology &#38 Therapeutics 01/2006; 79(2):P13-P13. · 6.85 Impact Factor
  • Article: PI24
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    ABSTRACT: Background/aims: Tamoxifen is widely used for the treatment and prevention of breast cancer. Endoxifen, one of its secondary metabolites, is formed by the genetically polymorphic CYP2D6 enzyme. Due to its high antiestrogenic potency, it may play an important role in the efficacy of tamoxifen. We conducted a prospective trial in 158 women with breast cancer to further understand the effect of CYP2D6 on the formation of endoxifen.Methods: Medication history and plasma concentrations of tamoxifen and its metabolites were determined at the fourth month of tamoxifen treatment. We also genotyped for 29 CYP2D6 alleles.Results: Mean endoxifen plasma concentration was significantly lower in CYP2D6 extensive metabolizers who were on CYP2D6 inhibitors than in those who were not on CYP2D6 inhibitors (39.5 vs. 71.5 nM, p < 0.01). This decrease was more pronounced with potent inhibitors of CYP2D6 such as paroxetine and fluoxetine than with weak CYP2D6 inhibitors (e.g. sertraline and citalopram). In fact, mean endoxifen plasma concentration in patients taking potent inhibitors was comparable to that in CYP2D6 poor metabolizers. Concomitant treatment with venlafaxine did not show any significant effect on mean endoxifen plasma concentration. Tamoxifen and its other metabolites were not affected by concurrent use of CYP2D6 inhibitors.Conclusions: Potent CYP2D6 inhibitors markedly reduce endoxifen plasma concentration, and may have a negative impact on the response to tamoxifen therapy.
    Clinical Pharmacology & Therapeutics - CLIN PHARMACOL THER. 01/2006; 79(2).
  • Article: OIV-B-3
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    ABSTRACT: Background/aims: N-Desmethyltamoxifen (NDM), a primary metabolite of tamoxifen, is hydroxylated by CYP2D6 to yield endoxifen, a potent antiestrogen. We hypothesized that endoxifen plasma concentration and the endoxifen/NDM plasma ratio reflect CYP2D6 activity and are associated with CYP2D6 genotype.Methods: We genotyped for 29 CYP2D6 alleles and determined plasma concentration of tamoxifen and its metabolites in 158 breast cancer patients after four months of tamoxifen therapy.Results: Using a mixture model approach, endoxifen plasma concentration identified two phenotypic groups, while four were defined by the endoxifen/NDM plasma ratio. All of the PM/PM, 83% of IM/PM and 75% of IM/IM genotypes belonged to the first endoxifen group, while 67% of EM/EM and 86% of UM/EM genotypes were part of the second phenotypic group. Three distinct genotype groups were identified in the distribution of endoxifen/NDM ratio: 1) low ratios composed of subjects lacking any functional allele; 2) intermediate ratios represented by subjects with one active allele; 3) high ratios composed of subjects with ≥2 functional alleles. Endoxifen/NDM plasma ratio was significantly different between groups.Conclusions: CYP2D6 genotype is highly associated with endoxifen plasma concentration and endoxifen/NDM plasma ratio. The endoxifen plasma concentration may be useful as a point of care test to optimize tamoxifen treatment. This approach may be valuable in the study of other complex genotype-phenotype relationships.
    Clinical Pharmacology &#38 Therapeutics 01/2006; · 6.85 Impact Factor
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    ABSTRACT: Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of dextromethorphan urinary metabolic ratio to predict dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with dextromethorphan oral clearance (r = 0.24; p = 0.04). In contrast, the dextromethorphan oral clearance was highly correlated with the dextromethorphan to dextrorphan area under the concentration-time curve ratio (r = 0.84; p = 0.005) and the 3-h (r = 0.60; p = 0.003), 4-h (r = 0.72, p < 0.001), 6-h (r = 0.67; p < 0.001), and 8-h (r = 0.74; p < 0.001) dextromethorphan to dextrorphan serum ratios. Assuming an effect size of 30%, the number of volunteers required for crossover and cross-sectional studies using the urinary metabolic ratio as the CYP2D6 index was calculated to be 56 and 524, respectively, whereas 14 and 60 subjects are needed if oral clearance is used. Considering the required sample size and the low correlation with oral clearance, urinary metabolic ratio is not recommended as the primary outcome variable in studies requiring the detection of modest changes in CYP2D6 activity.
    Drug Metabolism and Disposition 07/2005; 33(7):1052-5. · 3.36 Impact Factor
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    ABSTRACT: Background: Previous studies have evaluated the relationship between CYP2D6 genotype and its metabolic capacity with contradictory results. CYP2D6 activity in intermediate metabolizers appears to be allelic specific.Aims: To compare CYP2D6 activity in groups with one or two CYP2D6*1 alleles.Methods: Human liver microsomes (HLM) from 46 livers were genotyped for CYP2D6*3, *4, *6 and *8 nonfunctional alleles, and *10 and *17 dysfunctional alleles. Poor metabolizers (n=6) were excluded. CYP2D6 activity was determined using dextromethorphan (DTM) O-demethylation rate. DTM (2, 5, 10 and 15 M) was incubated with HLM (0.5 mg protein) for 7 min. Dextrorphan formation was measured by HPLC-fluorescence, with codeine as internal standard.Results: Twenty-five HLM were classified as extensive metabolizers (EM) and 15 as intermediate metabolizers (IM): *1/*4 (n=7), *1/*8 (n=2), *1/*10 (n=3), *1/*17 (n=2), *4/*17 (n=1). There was an extensive overlap in the activity between genotype groups. Vmax, intrinsic clearance (Clint) and Km in EM were not significantly different from IM. EM had a different Vmax from *1/*4 IM (p<0.05), Vmax and Clint from *1/*10 IM (p<0.05) and Km from *1/*17 IM (p<0.05). IM carrying one nonfunctional allele showed a significant difference in the Km from IM carrying one dysfunctional allele (p<0.01).Conclusions: Genotype did not predict CYP2D6 activity. The allele selective effect on CYP2D6 activity among IM may be explained by a difference in the expression and/or affinity of the enzyme.
    Clinical Pharmacology &#38 Therapeutics 01/2005; 77(2):P25-P25. · 6.85 Impact Factor