Frequency of CYP2D6*3 and *4 and metabolizer phenotypes in three mestizo Peruvian populations

Wild type genotypes (CYP2D6) and their allelic variants have been described in a sample of a Peruvian mestizo population. The global allele frequency was 0.015 for CYP2D6*3 and 0.051 for CYP2D6*4. The percentages of genotypes described were 97% CYP2D6*1/*1 and 3.0% CYP2D6*1/*3; 90.60% for CYP2D6*1/*1, 8.55% CYP2D6*1/*4 and 0.85% CYP2D6*4/*4. The allelic frequencies of CYP2D6*3 in the Lima subpopulations were 0.022 and 0.010 for Junin; CYP2D6*4 of 0.048, 0.060, and 0.050 for residents of Lima, Junín, and Tacna, respectively. The Hardy-Weinberg equilibrium test for the studied population showed that both frequencies are in equilibrium, p <.05. The metabolizer phenotype was inferred according to the genotypes: 11.54% were classified as intermediate metabolizers (*1/*3 or *1/*4) and 0.85% as poor metabolizers (*4/*4). It is concluded that the frequencies of the CYP2D6*3 and CYP2D6*4 alleles are low for the Peruvian mestizo population compared to the Latin American and tricontinental population, due to their natural population evolution, which is manifested by their decreased metabolic activity, the same that is relevant in clinical practice.

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Frequency of CYP1A1*2A polymorphisms and deletion of the GSMT1 gene in a Peruvian mestizo population

Pharmacia ◽

10.3897/pharmacia.68.e71621 ◽

2021 ◽

Vol 68 (4) ◽

pp. 747-754

Author(s):

Angel Tito Alvarado ◽

Ana María Muñoz ◽

María Saravia Bartra ◽

Milton Valderrama-Wong ◽

Daniela González ◽

...

Keyword(s):

Phase I ◽

Risk Allele ◽

Wild Type ◽

Metabolic Imbalance ◽

Environmental Component ◽

Hardy Weinberg Equilibrium ◽

Potential Risks ◽

Polymorphic Variants ◽

Equilibrium Test ◽

Phase I And Ii

The polymorphic variants of CYP1A1 and the deletion of GSTM1 are present in the Peruvian mestizo population. Wild type and mutated genotypes (WT/*2A and *2A/ *2A) were identified, whose allele frequencies are 0.31 (T allele) and 0.69 (C allele), respectively; 53% with wild type GSTM1 (+) and 47% with null GSTM1. The frequency in Iquiteño emigrants was 0.72 CYP1A1*2A and 25% GSTM1 (-); from Lima 0.67 CYP1A1*2A and 33% of GSTM1 (-). The Hardy-Weinberg equilibrium test for the studied population showed that both frequencies are out of balance, p > .05. The presence of the risk allele of the CYP1A1*2A polymorphism and the deletion in the GSTM1 gene are high, which could be indicative of a phase I and II metabolic imbalance in this group of Peruvian populations, with potential risks of activating agents procarcinogens thus affecting the incidence of tumor pathologies with an environmental component.

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CYP2C19 Polymorphisms in Indonesia: Comparison among Ethnicities and the Association with Clinical Outcomes

Biology ◽

10.3390/biology10040300 ◽

2021 ◽

Vol 10 (4) ◽

pp. 300

Author(s):

Muhammad Miftahussurur ◽

Dalla Doohan ◽

Ari Fahrial Syam ◽

Iswan Abbas Nusi ◽

Phawinee Subsomwong ◽

...

Keyword(s):

Proton Pump Inhibitor ◽

Clinical Outcomes ◽

Proton Pump ◽

Poor Metabolizers ◽

Wild Type Allele ◽

Wild Type ◽

Type Allele ◽

Sydney System ◽

Intermediate Metabolizers ◽

Cyp2c19 Polymorphisms

CYP2C19 polymorphisms are important factors for proton pump inhibitor-based therapy. We examined the CYP2C19 genotypes and analyzed the distribution among ethnicities and clinical outcomes in Indonesia. We employed the polymerase chain reaction-restriction fragment length polymorphism method to determine the CYP2C19 genotypes and evaluated inflammation severity with the updated Sydney system. For CYP2C19*2, 46.4% were the homozygous wild-type allele, 14.5% were the homozygous mutated allele, and 39.2% were the heterozygous allele. For CYP2C19*3, 88.6% were the homozygous wild-type allele, 2.4% were the homozygous mutated allele, and 9.0% were the heterozygous allele. Overall, the prevalence of rapid, intermediate, and poor metabolizers in Indonesia was 38.5, 41.6, and 19.9%, respectively. In the poor metabolizer group, the frequency of allele *2 (78.8%) was higher than the frequency of allele *3 (21.2%). The Papuan had a significantly higher likelihood of possessing poor metabolizers than the Balinese (OR 11.0; P = 0.002). The prevalence of poor metabolizers was lower compared with the rapid and intermediate metabolizers among patients with gastritis and gastroesophageal reflux disease. Intermediate metabolizers had the highest prevalence, followed by rapid metabolizers and poor metabolizers. Dosage adjustment should therefore be considered when administering proton pump inhibitor-based therapy in Indonesia.

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Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3577 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3577-3577

Author(s):

Stefano Mariani ◽

Marco Puzzoni ◽

Nicole Liscia ◽

Valentino Impera ◽

Andrea Pretta ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Practice ◽

Metastatic Colorectal Cancer ◽

Liquid Biopsy ◽

Selection Criteria ◽

Wild Type ◽

Braf Mutations ◽

Previous Response ◽

Clinical Variables ◽

Ct Dna

3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.

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Analysis of the metabolic activity of prolonged-acting fenfluramine in clinical practice

Current Medical Research and Opinion ◽

10.1185/03007997909117512 ◽

1979 ◽

Vol 6 (sup1) ◽

pp. 236-246 ◽

Cited By ~ 5

Author(s):

B. Riveiine

Keyword(s):

Clinical Practice ◽

Metabolic Activity

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Analysing CYP2D6*4 Allele frequency in Patients with Schizophrenia

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.314 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S101-S102

Author(s):

V. Djordjevic ◽

T. Jevtovic Stoimenov

Keyword(s):

Allele Frequency ◽

Plasma Concentrations ◽

Clinical Severity ◽

Genotype Distribution ◽

Healthy Individuals ◽

Wild Type ◽

Specific Pcr ◽

Significant Difference ◽

Schizophrenic Patients ◽

The Right

IntroductionSchizophrenia is treated with antipsychotics and other psychotropic medications, many of which are substrates for the highly polymorphic CYP2D6 enzyme. The most frequent variant allele is CYP2D6*4- leading cause of poor metabolism (PM) phenotype. PM causes the reduction of therapeutic response, increase the risk of adverse drug reactions and increase the plasma concentration of both drug and its metabolites above the levels of toxicity.The AimAnalysing CYP2D6*4 allele frequency among schizophrenic patients for further individualisation and rationalisation of therapy.Patients and methodsResearch was conducted on 38 schizophrenic patients and 110 healthy individuals. CYP2D6*4 allele was detected with allele specific PCR.ResultsBoth wild type allele carriers are 55% of the schizophrenic patients, 45% are wild type/*4heterozygous, and *4/*4 homozygous are not identified. There is a statistically significant difference in the genotype distribution (P < 0.05) between schizophrenic patients and healthy individuals. Significantly higher *4 allele frequency (37%) comparing to healthy individuals (P < 0.0001) indicates the necessary caution in administration of CYP2D6 substrates. A lower frequency of PMs in schizophrenic patients than in healthy individuals could be explained with CYP2D6 neuroactive substrate metabolism. Forty-five percent of the schizophrenic patients are intermediate metabolisers carrying the higher risk of adverse response to CYP2D6 substrates comparing to wild type homozygous. As none of the analyzed patients was PM, exceeded plasma concentrations of medications above toxic levels are not expected when administrating the right dosage.ConclusionAltered CYP2D6 metabolism may contribute to the vulnerability, clinical severity and treatment outcome of schizophrenia.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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