Effects of CYP2D6 and UGT2B7 polymorphisms on pharmacokinetics of tamoxifen in Thai breast cancer patients

Areepium, Nutthada; Panomvana, Duangchit; Rungwanonchai, Pichayapa; Sathaporn, S; Voravud, Narin

doi:10.2147/bctt.s47172

Cited by 12 publications

(21 citation statements)

References 20 publications

(33 reference statements)

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“… 33 – 35 The prevalence of UGT1A1 * 6 , which is more commonly observed in Asian populations and absent among Caucasians, resembled earlier studies that reported a frequency of 9%. 36 A previous study of UGT2B7 * 2 among Thai patients with breast cancer reported an allele frequency of 28%, 37 which is similar to the 31.5% reported in this study. CYP1A2 * 1F was associated with an increased risk of cholangiocarcinoma (CCA), while NAT2 * 6 and * 7 were associated with a lower risk of CCA in a study by Prawan et al, 38 who evaluated the relationship between CYP1A2 and NAT2 alleles and CCA among individuals living in the northeastern region of Thailand.…”

Section: Discussionsupporting

confidence: 86%

Clinically relevant genetic variants of drug-metabolizing enzyme and transporter genes detected in Thai children and adolescents with autism spectrum disorder

Medhasi¹,

Pasomsub²,

Vanwong³

et al. 2016

NDT

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Single-nucleotide polymorphisms (SNPs) among drug-metabolizing enzymes and transporters (DMETs) influence the pharmacokinetic profile of drugs and exhibit intra- and interethnic variations in drug response in terms of efficacy and safety profile. The main objective of this study was to assess the frequency of allelic variants of drug absorption, distribution, metabolism, and elimination-related genes in Thai children and adolescents with autism spectrum disorder. Blood samples were drawn from 119 patients, and DNA was extracted. Genotyping was performed using the DMET Plus microarray platform. The allele frequencies of the DMET markers were generated using the DMET Console software. Thereafter, the genetic variations of significant DMET genes were assessed. The frequencies of SNPs across the genes coding for DMETs were determined. After filtering the SNPs, 489 of the 1,931 SNPs passed quality control. Many clinically relevant SNPs, including CYP2C19*2, CYP2D6*10, CYP3A5*3, and SLCO1B1*5, were found to have frequencies similar to those in the Chinese population. These data are important for further research to investigate the interpatient variability in pharmacokinetics and pharmacodynamics of drugs in clinical practice.

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Section: Discussionsupporting

confidence: 86%

Clinically relevant genetic variants of drug-metabolizing enzyme and transporter genes detected in Thai children and adolescents with autism spectrum disorder

Medhasi¹,

Pasomsub²,

Vanwong³

et al. 2016

NDT

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“… 30 CYP2D6*10 /* 10 , a common reduced-activity allele in Asians including Thais, was demonstrated to be associated with significantly lower endoxifen level compared to CYP2D6*1 /* 1 at steady-state of tamoxifen adjuvant therapy. 8 , 31 , 32 Consequently, Asian women carrying CYP2D6*10/*10 genotype had significantly shorter DFS than those who carry CYP2D6*1/*1 genotype treated with the equivalent dose of tamoxifen. 6 , 7 , 10 , 31 Furthermore, CYP2D6*10/*10 was independently correlated to unfavorable outcomes in tamoxifen treatment, significant in the multivariate analyses adjusted for clinical prognostic factors.…”

Section: Discussionmentioning

confidence: 97%

ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen

Sensorn

Sukasem

Sirachainan

et al. 2016

OTT

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BackgroundGenetic polymorphisms of drug-metabolizing enzymes and transporters have been extensively studied with regard to tamoxifen treatment outcomes. However, the results are inconclusive. Analysis of organ-specific metastasis may reveal the association of these pharmacogenetic factors. The aim of this study is to investigate the impact of CYP3A5, CYP2D6, ABCB1, and ABCC2 polymorphisms on the risk of all distant and organ-specific metastases in Thai patients who received tamoxifen adjuvant therapy.MethodsGenomic DNA was extracted from blood samples of 73 patients with breast cancer who received tamoxifen adjuvant therapy. CYP3A5 (6986A>G), CYP2D6 (100C>T), ABCB1 (3435C>T), and ABCC2 (−24C>T) were genotyped using allelic discrimination real-time polymerase chain reaction assays. The impacts of prognostic clinical factors and genetic variants on disease-free survival were analyzed using the Kaplan–Meier method and Cox regression analysis.ResultsIn the univariate analysis, primary tumor size >5 cm was significantly associated with increased risk of distant metastasis (P=0.004; hazard ratio [HR] =3.05; 95% confidence interval [CI], 1.44–6.47). In the multivariate analysis, tumor size >5 cm remained predictive of distant metastasis (P<0.001; HR=5.49; 95% CI, 2.30–13.10). ABCC2 −24CC were shown to be associated with increased risk of distant metastasis (P=0.040; adjusted HR=2.34; 95% CI, 1.04–5.27). The combined genotype of ABCC2 −24CC − ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15–5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06–12.89, respectively).ConclusionThis study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis. Further prospective studies with larger sample sizes are needed to verify this finding.

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“…The prevalence and type of incomplete functional allele (null allele and reduced allele) that is involved in CYP450 enzyme activity are different in different populations;14 the prevalence of CYP2D6*4 (null allele) has been found to be higher in Caucasians15 than in Asians16 or Thais,17 while that of CYP2D6*10 (reduced allele) has been found to be higher in Asians,16 including Thais,18 than in Caucasians15 and CYP3A5*3 (null allele) is the major allele in Caucasians15 and Asians,16 including Thais 18. Previous research has suggested that the low activities of CYP2D6 and CYP3A5 enzymes account for 25%–55% and 40%–50% of the polymorphisms, respectively, in Thai breast cancer patients 17–19. Early researches suggested that CYP2D6*10/*10 patients had shorter disease-free survival than heterozygous CYP2D6*10 ( p =0.046)17 and lower END concentrations than those patients with CYP2D6*1/*10 and CYP2D6*1/*1 ( p =0.045)19 among Thai breast cancer patients; however, the result was not completely generalized to target population because of the limited sample size 19.…”

Section: Introductionmentioning

confidence: 99%

Effects of <em>CYP2D6 </em>and <em>CYP3A5 </em>polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

Charoenchokthavee¹,

Areepium²,

Panomvana³

et al. 2017

BCTT

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PurposeThis study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations.Patients and methodsOne hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal–Wallis or Mann–Whitney U test, including the simple main effects analysis.ResultsThe patients had stage 0–IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype.ConclusionCYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group.

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Effects of CYP2D6 and UGT2B7 polymorphisms on pharmacokinetics of tamoxifen in Thai breast cancer patients

Cited by 12 publications

References 20 publications

Clinically relevant genetic variants of drug-metabolizing enzyme and transporter genes detected in Thai children and adolescents with autism spectrum disorder

Clinically relevant genetic variants of drug-metabolizing enzyme and transporter genes detected in Thai children and adolescents with autism spectrum disorder

ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen

Effects of <em>CYP2D6 </em>and <em>CYP3A5 </em>polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

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