CYP2C19 Genotyping May Provide a Better Treatment Strategy when Administering Escitalopram in Chinese Population

Depression disorder is one of the most serious mental illnesses in the world. Escitalopram is the essential first-line medication for depression disorder. It is the substrate of hepatic cytochrome P450 (CYP) enzyme CYP2C19 with high polymorphism. The effect of CYP2C19 on pharmacokinetics and pharmacodynamics on Caucasian population has been studied. The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population. However, the gene frequency of the alleles of CYP2C19 showed racial differences between Chinese and Caucasian populations. Representatively, the frequency of the *2 and *3 allele, which were considered as poor metabolizer, has been shown to be three times higher in Chinese than in Caucasians. In addition, the environments might also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. It is necessary to provide the evidence of individual treatment of escitalopram in Chinese by studying the effect of CYP2C19 genotypes on the pharmacokinetics parameters and steady-state concentration on Chinese. In this study, single-center, randomized, open-label, two-period, two-treatment crossover studies were performed. Ninety healthy Chinese subjects finished the trials, and they were included in the statistical analysis. The pharmacokinetics characteristics of different genotypes in Chinese were obtained. The results indicate that the poor metabolizer had higher exposure, and increased half-life than the extensive metabolizer and intermediate metabolite. The prediction of steady-state concentration based on the single dose trial on escitalopram shows that the poor metabolizer might have a higher steady-state concentration than the extensive metabolizer and intermediate metabolite in Chinese. The results indicate that the genetic testing before medication and the adjustment of escitalopram in the poor metabolizer should be considered in the clinical treatments in Chinese. The results provide the evidence of individual treatment of escitalopram in Chinese, which will be beneficial for the safer and more effective application of escitalopram in the Chinese population.Clinical Trial Registration: identifier ChiCTR1900027226.

ANALISIS POLIMORFISME CYP2D6*4 DAN CYP2D6*10 SEBAGAI METABOLIZER PRIMAKUIN DI RSUD JAYAPURA PAPUA INDONESIA

Primakuin adalah antimalaria yang digunakan untuk mengeliminasi stadium gametosit Plasmodium falciparum dan stadium hipnozoit dari P. vivax. Efektivitas primakuin dipengaruhi oleh kemampuan individu dalam memetabolisme obat. Metabolisme primakuin utama diperankan melalui jalur enzim sitokrom P 450 2D6. Polimorfisme gen pengkode enzim tersebut, yakni gen CYP2D6 berdampak pada perubahan dalam kemampuan memetabolisme obat. Tujuan penelitian ini adalah untuk mengetahui distribusi genotipe dan frekuensi alotipe dari CYP2D6*4(G/A) dan CYP2D6*10(C/T). Metode yang digunakan untuk menilai polimorfisme pada penelitian ini adalah PCR-RFLP dengan desain penelitian deskriptif observasional. Hasil penelitian menunjukkan bahwa alel CYP2D6*4 yang dapat bermanifestasi sebagai poor metabolizer tidak ditemukan pada sampel penelitian. Frekuensi alel CYP2D6*10 yang dapat bermanifestasi sebagai intermediete metabolizer adalah 10%. Genotipe homozigot mutan CYP2D6*4 dan CYP2D6*10 tidak ditemukan pada penelitian ini. 100% sampel penelitian ini memiliki kemampuan metabolisme yang baik (extensive metabolizer) terhadap primakuin.

Effect of CYP2D6 genetic polymorphism on peak propafenone concentration: no significant effect of CYP2D6*10

Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.

Chloroquine Phosphate Metabolism and Gender-based Phenotypic Analysis in Healthy Subjects’ Urine Following Oral Administration

Background: Chloroquine, 4-N-(7-chloroquinolin-4-yl)-1-N,-N-diethylpentane-1,4-diamine has promising activity against corona virus disease 2019 (COVID-19) and as such, it is imperative to thoroughly understand and determine the rate at which individual body systems metabolizes the drug. Chloroquine a known antimalarial drug belongs to the chemical class of 4-aminoquinolines. Objectives: The study aimed to analyze Chloroquine and its metabolite in biological fluids of healthy subjects by simple thin layer chromatography (TLC), which is an efficient, and inexpensive method for quantifying Chloroquine and its metabolites. Methods: A total of 30 healthy volunteers participated in the study by ingesting 500 mg of chloroquine, and the results were compared with side effects experienced by these subjects. Two brands of Chloroquine phosphate were used for the analysis and the urine were collected pre and post-drug administration and the intensities of the spots observed were compared with the reference standard stock solution. The same or greater intensity of sample spot indicates poor metabolizer, less intensity when compared to the stock spot indicates intermediate metabolizer while a much lesser intensity indicates an extensive metabolizer. Results: There was a statistically significant difference between the brands of chloroquine used at P<0.05. 30% of the volunteers were assigned poor metabolizer phenotype, 50% were assigned extensive metabolizer phenotype, and 20% assigned Intermediate metabolizer phenotype based on the intensity of spots observed. The majority of the poor metabolizers were females while the majority of the extensive metabolizers were males. Conclusion: Gender differences plays a vital the role in metabolism, therefore outine implementation of phenotype determination before therapy will therefore greatly improve the goal of therapy and quality of life. implementation of phenotype determination before therapy will, therefore, greatly improve the goal of therapy and quality of life.

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

Accurate determination of the CYP2D6 (*1/*4)xN genotype by quantitative PCR

Background: CYP2D6 is responsible for the metabolism of approximately 25% of all drugs. The expression of cytochrome P450 2D6 (CYP2D6) is influenced by a combination of factors including polymorphisms in the CYP2D6 gene. Analysis of the CYP2D6 genotype is used to personalize the medication to a patient’s metabolism. Although many genotypes can be determined using standard genotype analysis, in some cases, an incomplete analysis is performed. The CYP2D6 genotype *1/*4 often occurs in combination with a multiplication of the CYP2D6 gene, and is reported as (*1/*4)xN. Accurate determination of the multiplied gene is essential to provide a phenotype prediction for these patients. Duplication of the *1 gene leads to an extensive metabolizer genotype whereas multiplication of the *4 gene would not lead to extra functional enzyme and therefore provides an intermediate metabolizer phenotype. Methods: Here, a technique is described in which the copy numbers of both the *4 and *1 genes are determined using quantitative PCR techniques. Results and conclusions: This technique provides a method to predict the patient’s CYP2D6 phenotype, and is therefore an important step toward personalized medicine.

Initial evaluation of the relationship between CYP2C19 polymorphisms and platelet aggregation in patients with acute myocardial infraction in some hospitals in Hanoi

CYP2C19 is one of the pricipal enzymes involed in the antiplatelet prodrug in patients with acute myocardial infraction. Different genotypes can cause various responses to platelet aggregation inhibitors. Therefore, we conduct research to evaluate the relationship between CYP2C19 polymorphisms and platelet aggregation in patients with acute myocardial infraction. The study was processed with a cross-sectional study of patients diagnosed acute myocardial infraction had blood samples tested for the gene CYP2C19 and platelet aggregation. The results in 64 consecutive patients, phenotypes based on genotypes: 59,3% poor and intermediate metabolizer, 40,7% extensive metabolizer. The average platelet aggregation of (poor, intermediate) metabolizer and extensive metabolizer were 29,79±13,6 and 23,27±11,6, respectively, there was a high similarity between the groups (p>0,05). The average platelet aggregation of (poor, intermediate) metabolier and extensive metabolizer on the group with Clopidogrel were 26,2±10,5 and 29,9±13,6 (p>0,05), the average with Ticagrelor were 10,8±6,5 and 18,4±8,7 (p>0,05), respectively. The group treated with Ticagrelor had a lower platelet aggregation than the remaining one with Clopidogrel (p<0,01). The study got some initial results that would be important for further studies on the relationship between CYP2C19 polymorphisms and platelet aggregation on Viet Namese patients with acute myocardial infraction.