Functional polymorphism of CYP2B6 G15631T is associated with hematologic and cytogenetic response in chronic myeloid leukemia patients treated with imatinib

Kassogue, Yaya; Quachouh, Meryem; Dehbi, Hind; Quessar, Asmaa; Benchekroun, Saïd; Nadifi, Sellama

doi:10.1007/s12032-013-0782-6

Cited by 18 publications

(8 citation statements)

References 33 publications

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“…The frequency of the CYP2B6 -rs3745274 mutant T allele observed in the Malian population was 37%, which is comparable to those observed in Central Africa (Cameroon 37%), [26] East Africa (Tanzania) 34%, [26] South Africa 36% [26] and in West African countries including Ivory Coast (38%), [27] Nigeria (36.3%), [28] and Ghana (46%) [29,30] . Looking at data from North Africa, we found that the frequency observed in Mali was statistically higher than that reported is Egypt (28.8%) P = .03, [31] but lower than that observed in the Moroccan population (55.5%) P = .000 [15] . As for CYP2B6- rs2279343, the frequency of the mutant G allele was 38% in the Malian population.…”

Section: Discussionmentioning

confidence: 67%

“…[6][7][8] The human CYP450 superfamily consists of 18 families, 42 subfamilies with 59 active genes. [9] Among these, the CYP2B6 and CYP3A4 families have been widely explored in genetic association studies for multifactorial diseases such as gout, [10] acute myeloid leukemia, [11] chronic obstructive pulmonary disease [12] as well than in pharmacogenetic studies including antiretrovirals (nevirapine, efavirenz), [13] antimalarial (artemisinin), [14] anticancer (chronic myeloid leukemia) [15] and anesthetics (propofol). [16] The CYP2B6 and CYP3A4 genes are located on the long arms of chromosomes 19q13.2 and 7q22.1 respectively.…”

Section: Introductionmentioning

confidence: 99%

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Distribution of alleles, genotypes and haplotypes of the CYP2B6 (rs3745274; rs2279343) and CYP3A4 (rs2740574) genes in the Malian population

et al. 2021

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Cytochrome P450 enzymes play a central role in the phase I biotransformation process of a wide range of compounds, including xenobiotics, drugs, hormones and vitamins. It is noteworthy that these enzymes are highly polymorphic and, depending on the genetic makeup, an individual may have impaired enzymatic activity. Therefore, the identification of genetic variants in these genes could facilitate the implementation of pharmacogenetic studies and genetic predisposition to multifactorial diseases. We have established the frequencies of CYP2B6 (rs3745274; rs2279343) and CYP3A4 (rs2740574) alleles and genotypes in 209 healthy Malian subjects using TaqMan drug metabolism genotyping assays for allelic discrimination. Allele frequencies were 37% for CYP2B6 rs3745274; 38% for CYP2B6 rs2279343; and 75% for CYP3A4 rs2740574 respectively. Overall, the frequencies observed in Mali are statistically comparable to those reported across Africa except North Africa. The major haplotypes in CYP2B6 rs3745274 and CYP2B6 rs2279343 were represented by GA (60.24%) followed by TG (35.36%). We noted a strong linkage disequilibrium between CYP2B6 rs3745274 and CYP2B6 rs2279343 with D' = 0.91 and r 2 = 0.9. The frequencies of the genotypic combinations were 43.5% (GT/AG), 37.3% (GG/AA) and 11.5% (TT/GG) in the combination of CYP2B6-rs3745274 and CYP2B6-rs2279343; 26.8% (GT/CC), 25.4%, (GT/CT), 17.2% and GG/CT in the combination CYP2B6-rs3745274-CYP3A4-rs2740574; 26.8% (AG/CC), 23.9% (AA/CC), 19.1% (AG/CT), and 11% (AA/CT) in the combination CYP2B6-rs2279343-CYP3A4-rs2740574, respectively. The most common triple genotype was GT/AG/CC with 24.9%, followed by GG/AA/CC with 23.9%, GT/AG/CT with 16.7%, and GG/AA/CT with 10%. Our results provide new insights into the distribution of these pharmacogenetically relevant genes in the Malian population. Moreover, these data will be useful for studies of individual genetic variability to drugs and genetic predisposition to diseases.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Distribution of alleles, genotypes and haplotypes of the CYP2B6 (rs3745274; rs2279343) and CYP3A4 (rs2740574) genes in the Malian population

et al. 2021

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“…This was under the consideration that ABCB1 (P-glycoprotein), as an efflux transporter of imatinib, is highly expressed in intestinal epithelium and liver cells, influencing absorption and biliary elimination by pumping out xenobiotics [38]. All other genotypes were tested as potential covariates of CL because of their potential involvement in the metabolism of imatinib [39][40][41]. None of the potential demographic covariates (body weight, BMI, BSA and gender) showed a statistically significant association with the individual PK parameters.…”

Section: Discussion Poppk Model For Healthy Volunteersmentioning

confidence: 99%

Population pharmacokinetic modelling of imatinib in healthy subjects receiving a single dose of 400 mg

Chien

Würthwein

Zubiaur

et al. 2022

Cancer Chemother Pharmacol

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Purpose Imatinib is indicated for treatment of CML, GIST, etc. The population pharmacokinetics (popPK) of imatinib in patients under long-term treatment are reported in literature. Data obtained from bioequivalence trials for healthy subjects were used to evaluate the influence of demographic and pharmacogenetic factors on imatinib pharmacokinetics (PK) in a collective without concurrent drugs, organ dysfunction, inflammation etc. In addition, the differences in PK between the healthy subjects and a patient cohort was examined to identify possible disease effects. Methods 26 volunteers were administered orally with single dose of 400 mg imatinib. 16–19 plasma samples per volunteer were collected from 0.5 up to 72 h post-dose. The popPK was built and post hoc estimates were compared with previously published PK parameters evaluated by non-compartmental analysis in the same cohort. The predictivity of the model for data collected from 40 patients with gastrointestinal stromal tumors at steady state was evaluated. Results The popPK was best described by a two-compartment transit model with first-order elimination. No significant covariates were identified, probably due to the small cohort and the narrow range of demographic covariates; CYP3A5 phenotypes appeared to have some influence on the clearance of imatinib. Good agreement between non-compartment and popPK analyses was observed with the differences of the geometric means/ median of PK estimates below 10%. The model indicated lower clearance for patients compared to healthy volunteers (p value < 0.01). Conclusion The two-compartment transit model adequately describes the absorption and distribution of imatinib in healthy volunteers. For patients, a lower clearance of imatinib compared to healthy volunteer was estimated by the model. The model can be applied for dose individualization based on trough concentrations assuming no significant differences in absorption between patients and healthy volunteers.

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“…In turn, homozygous patients with the CYP3A5 *3 genotype may experience reduced enzyme activity, leading to the limited clearance and high bioavailability of the drug, and the subsequent better response to IM, but also a possibly increased risk of adverse events. Another study which assessed the functional impact of CYP2B6 15631G/T polymorphism on the response of imatinib in CML patients demonstrated the relationship between a higher hematologic response and the presence of the 15631GG/TT genotype compared to 15631GT (36.8 vs. 13.8%; χ 2 = 3.542, p = 0.063) [ 210 ]. However, the complete cytogenetic response was better in patients carrying the 15631GG/GT genotype when compared with 15631TT (χ 2 = 3.298, p = 0.024), while the primary cytogenetic resistance was greater in those with the 15631GG/TT genotype when compared with 15631GT carriers (52.6 vs. 17.2%; χ 2 = 6.692, p = 0.010).…”

Section: The Impact Of Genetic Variations On Anticancer Treatment Eff...mentioning

confidence: 99%

Pharmacogenetics of Drugs Used in the Treatment of Cancers

Franczyk

Rysz

Gluba-Brzózka

2022

Genes

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Pharmacogenomics is based on the understanding of the individual differences in drug use, the response to drug therapy (efficacy and toxicity), and the mechanisms underlying variable drug responses. The identification of DNA variants which markedly contribute to inter-individual variations in drug responses would improve the efficacy of treatments and decrease the rate of the adverse side effects of drugs. This review focuses only on the impact of polymorphisms within drug-metabolizing enzymes on drug responses. Anticancer drugs usually have a very narrow therapeutic index; therefore, it is very important to use appropriate doses in order to achieve the maximum benefits without putting the patient at risk of life-threatening toxicities. However, the adjustment of the appropriate dose is not so easy, due to the inheritance of specific polymorphisms in the genes encoding the target proteins and drug-metabolizing enzymes. This review presents just a few examples of such polymorphisms and their impact on the response to therapy.

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Functional polymorphism of CYP2B6 G15631T is associated with hematologic and cytogenetic response in chronic myeloid leukemia patients treated with imatinib

Cited by 18 publications

References 33 publications

Distribution of alleles, genotypes and haplotypes of the CYP2B6 (rs3745274; rs2279343) and CYP3A4 (rs2740574) genes in the Malian population

Distribution of alleles, genotypes and haplotypes of the CYP2B6 (rs3745274; rs2279343) and CYP3A4 (rs2740574) genes in the Malian population

Population pharmacokinetic modelling of imatinib in healthy subjects receiving a single dose of 400 mg

Pharmacogenetics of Drugs Used in the Treatment of Cancers

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