Frequency Of Poor Metabolizers Research Articles

Effect of CYP2D6, 2C19, and 3A4 Phenoconversion in Drug-Related Deaths.

Molecular autopsy is a very important tool in forensic toxicology. However, many determinants, such as co-medication and physiological parameters, should be considered for optimal results. These determinants could cause phenoconversion (PC), a discrepancy between the real metabolic profile after phenoconversion and the phenotype determined by the genotype. This study's objective was to assess the PC of drug-metabolizing enzymes, namely CYP2D6, 2C19, and 3A4, in 45 post-mortem cases where medications that are substrates, inducers, or inhibitors of these enzymes were detected. It also intended to evaluate how PC affected the drug's metabolic ratio (MR) in four cases. Blood samples from 45 cases of drug-related deaths were analyzed to detect and determine drug and metabolite concentrations. Moreover, all the samples underwent genotyping utilizing the HaloPlex Target Enrichment System for CYP2D6, 2C19, and 3A4. The results of the present study revealed a statistically significant rate of PC for the three investigated enzymes, with a higher frequency of poor metabolizers after PC. A compatibility was seen between the results of the genomic evaluation after PC and the observed MRs of venlafaxine, citalopram, and fentanyl. This leads us to focus on the determinants causing PC that may be mainly induced by drug interactions. This complex phenomenon can have a significant impact on the analysis, interpretation of genotypes, and accurate conclusions in forensic toxicology. Nevertheless, more research with more cases in the future is needed to confirm these results.

Polymorphisms in CYP2C8 Gene in Pakistani Population and Their Frequencies in Various Ethnic Groups

Cytochrome P4502C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in the metabolism of endogenous compounds. More than 20 single nucleotide polymorphisms (SNPs) have been reported, mainly in exon 3, 5, and 8. Some of the SNP’s lead to decreased enzyme activity and may have impact on drug metabolism. This research study aims to determine the frequencies of the most common SNPs of the CYP2C8 gene (CYP2C8*2, *3, *4) in the Pakistani population. A cross-sectional study consisting of 391 healthy humans was conducted after taking informed consent. DNA was extracted using commercial kits, and allelic and genotype frequencies were determined after PCR amplification, restriction fragment length polymorphism, and gel electrophoresis. The rate of minor allele was found to be 11.64% for CYP2C8*2, 14.71% for CYP2C8*3, and 1.53% for CYP2C8*4. Comparison with the 1000 Genome project reveals that the allelic frequencies of CYP2C8*4 in Pakistani population were similar to other South Asian populations while the frequencies of CYP2C8*2 and CYP2C8*3 as significantly different from other South Asian populations. A significant interethnic variation was also observed among Pakistani ethnicities. The CYP2C8*2 allele was highest in the Sindhi population, CYP2C8*3 in the Pashtoon population and CYP2C8*4 in the Balochi population. These data suggest that the frequency of poor metabolizers of CYP2C8 is high enough in the Pakistani population to warrant further genotype-phenotype correlations studies on individual drugs metabolized by CYP2C8 enzyme.

Allelic and genotype frequencies of major CYP2B6 polymorphisms in the Pakistani population.

BackgroundCytochrome P450 (CYP2B6) is an important enzyme that metabolizes about 3.0% of therapeutic drugs. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. The genetic polymorphisms in the CYP2B6 gene have earlier been studied in many populations, but the data are lacking for the Pakistani population. This research study aimed to determine the frequencies of the three of the most important variant alleles and genotypes of the CYP2B6 gene in the Pakistani population.MethodsBlood was withdrawn from healthy volunteers after taking informed consent. DNA was extracted using commercial kits, and allelic and genotype frequencies were determined after PCR amplification followed by restriction fragment length polymorphism (RFLP) and gel electrophoresis.ResultsOur results show a minor allele frequency of 33.8% for CYP2B6*6, 25.8% for CYP2B6*4, 6.5% for CYP2B6*3, whereas wild‐type genotype frequency was 48.57% for CYP2B6*6, 59.79% for CYP2B6*4, and 90.20% for CYP2B6*3. A significant interethnic variation was also observed.ConclusionsOur results suggest that the frequency of poor metabolizers of CYP2B6, especially *6 variant, is significant enough in the Pakistani population to be given an important consideration when drugs metabolized by this enzyme are prescribed.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas.

In previous CYP2D6 genotyping studies in Mexican-Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. In the present study we evaluated the hypothesis of low frequency of PMs in Mexican-Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican-Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations.

Analysis of the CYP2C19 genetic polymorphism in Han and Uyghur patients with cardiovascular and cerebrovascular diseases in the Kashi area of Xinjiang.

BackgroundThe aim of this study was to analyze the CYP2C19 genetic polymorphism among Han and Uyghur patients with cardiovascular and cerebrovascular diseases in the Kashi area of Xinjiang.Material/MethodsWe enrolled 1020 patients with cardiovascular and cerebrovascular diseases, including 220 Han subjects and 800 Uyghur subjects. We used the gene chip method to detect polymorphisms in CYP2C19. The allele frequencies of CYP2C19 and the metabolic phenotype frequencies were then compared between the 2 ethnic groups.ResultsThe frequency of CYP2C19 *1 was 0.6454 in Han subjects and 0.7869 in Uyghur subjects, and the difference was statistically significant (P<0.05). The frequency of CYP2C19 *2 was 0.3273 in Han subjects and 0.1837 in Uyghur subjects (P<0.05). The frequency of the homozygous extensive metabolizer phenotype was 42.72% and 62.13% in Han and Uyghur subjects, respectively (P<0.01). The frequency of the heterozygous extensive metabolizer phenotype was 43.64% and 33.13% in Han and Uyghur subjects, respectively (P<0.01). The frequency of poor metabolizers in Han and Uyghur subjects was 13.64% and 4.76%, respectively (P<0.01).ConclusionsAmong patients with cardiovascular and cerebrovascular diseases located in the Kashgar Prefecture of Xinjiang, there is a differential distribution of CYP2C19 genotypes between the Han and Uyghur populations. Uyghur patients showed higher frequencies of extensive metabolizer genotypes than Han patients, while Han patients showed higher frequencies of poor metabolizer genotypes than Uyghur patients.

CYP2C19 polymorphisms in the Thai population and the clinical response to clopidogrel in patients with atherothrombotic-risk factors

Genetic variation in the cytochrome P450 2C19 (CYP2C19) gene has been documented gradually as the determinant conversion and variability in the antiplatelet effect of clopidogrel. The aims of this study were to determine the prevalence of clinically relevant allele variants (CYP2C19*2, CYP2C19*3, and CYP2C19*17) in a Thai study population, and finally determine whether the allele distributes and predicts metabolic phenotypes in clopidogrel treated patients. A total of 1,051 Thai patients participated in this study. Genotypes for CYP2C19 polymorphisms were detected by the microarray-based technique. Furthermore, results of genotyping and platelet aggregation in 96 cardiovascular disease patients on 75 mg clopidogrel maintenance daily dose therapy also were analyzed. Among 1,051 samples, the allele frequencies of CYP2C19 *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *1/*17 were found in 428 (40.72%), 369 (35.10%), 72 (6.85%), 77 (7.32%), 59 (5.61%), and 45 (4.30%) of the patients, respectively. Homozygous CYP2C19 *3/*3 was found in one patient (0.10%). Therefore, 40.72% of the patients were predicted as extensive metabolizers, 41.95% as intermediate metabolizers, 13.03% as poor metabolizers, and 4.30% as ultra-rapid metabolizers. Among 96 patients, the frequency of poor metabolizers was significantly higher in the clopidogrel non-responder group than in the responder group (36.0% and 15.5%, respectively, P = 0.03). CYP2C19*1/*17 was observed in responders (n = 2; 2.8%). As a result, CYP2C19 variants were associated with clopidogrel non-responders. However, there is a need for further elucidation of the clinical importance and use of this finding to make firm and cost-effective recommendations for drug treatment in the future.

CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans

CYP2D6 genotype and debrisoquine metabolic ratio (MR) were analyzed in 133 Nicaraguan Mestizos (NMs) and 260 Cubans divided into Cuban Mestizos (CMs) and White Cubans (WCs). The frequencies of poor metabolizers (MR12.6) were 6% in NMs, 3.9% in CMs and 5.3% in WCs. The frequencies of ultrarapid metabolizers (MR0.1) were 0% in NMs, 2.3% in CMs and 5.3% in WCs. Mean (±s.d.) MR among extensive metabolizers (MR<12.6) was higher in NMs (1.5±1.6; n=118) than in CMs (1.0±1.3; n=124; P<0.001) and WCs (0.7±1.0; n=124; P<0.001). MR correlated with the 'activity score' of CYP2D6 genotypes (P<0.05; r=-0.55). Mean MR was higher among NMs than WCs and CMs for groups classified as 1 (P<0.05) or 2 (P<0.01) 'activity score'. In addition, mean (±s.d.) MR was higher among subjects carrying CYP2D6*17 than in CYP2D6 wt/wt (P<0.001). The CYP2D6*10 allele was higher in NMs (3.1%) than in CMs (0.8%; P<0.05) and WCs (0.4%; P<0.05). CYP2D6*17 allele was higher in CMs (10.2%) than WC (2.7%; P<0.005) and NMs (0%). Thus, the variability in CYP2D6 phenotypes found may be related to differences in allele frequency among groups (that is, CYP2D6*10 and *17 highest in NMs and CMs, respectively). However, the influence of environmental factors or alleles different than those studied here cannot be ruled out.

Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals

BackgroundOmeprazole is metabolized by the hepatic cytochrome P450 (CYP) 2C19 enzyme to 5-hydroxyomeprazole. CYP2C19 exhibits genetic polymorphisms responsible for the presence of poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers (EMs). The defective mutations of the enzyme and their frequencies change between different ethnic groups; however, the polymorphism of the CYP2C19 gene has not been studied in Colombian mestizos. The aim of this study was to evaluate the genotype and phenotype status of CYP2C19 in Colombian mestizos, in order to contribute to the use of appropriate strategies of drug therapy for this population.Methods189 subjects were genotyped using the multiplex SNaPshot technique and a subgroup of 44 individuals received 20 mg of omeprazole followed by blood collection at 3 hours to determine the omeprazole hydroxylation index by HPLC.Results83.6%, 15.3% and 1.1% of the subjects were genotyped as EMs, IMs and PMs, respectively. The frequencies of the CYP2C29*1 and CYP2C19*2 alleles were 91.3% and 8.7% respectively whereas the *3, *4, *5, *6 and *8 alleles were not found. No discrepancies were found between the genotype and phenotype of CYP2C19.ConclusionThe frequency of poor metabolizers (1.1%) in the Colombian mestizos included in this study is similar to that in Bolivian mestizos (1%) but lower than in Mexican-Americans (3.2%), West Mexicans (6%), Caucasians (5%) and African Americans (5.4%). The results of this study will be useful for drug dosage recommendations in Colombian mestizos.

CYP2C19 GENOTYPE AND OMEPRAZOLE HYDROXYLATION PHENOTYPE IN CHINESE LI POPULATION

1. CYP2C19 is a polymorphism of cytochrome P450, which is responsible for the metabolism of many drugs. The genetic polymorphism shows interethnic variation and it has been demonstrated that the frequency of poor metabolizers (PM) and the distribution of alleles of CYP2C19 vary among Chinese ethnic nationalities. The aim of the present study was to investigate the incidence of CYP2C19 polymorphism in the Chinese Li population. 2. One hundred and sixty-five unrelated healthy Li subjects were identified with respect to CYP2C19 by genotype and phenotype analysis. A polymerase chain reaction-restriction fragment length polymorphism method was performed for genotyping. The plasma concentrations of omeprazole and 5-hydroxyomeprazole were assayed by reversed-phase high-performance liquid chromatography and the omeprazole hydroxylation index (HI) was determined. 3. The frequency distribution of omeprazole HI is bimodal and the antimode for HI was estimated to be 5.6. The prevalence of phenotypic PM in the Li population was 16.6% (13.7-19.5; 95% CI). Genotype analysis revealed that the frequencies of the CYP2C19*1, *2 and *3 alleles in the Li population were 0.617 (0.590-0.644; 95% CI), 0.353 (0.327-0.379; 95% CI) and 0.031 (0.021-0.041; 95% CI), respectively. The frequency of genotypic PM was 14.7% (11.9-17.5; 95% CI), which almost agreed with the frequency of phenotypic PM. Omeprazole HI was significantly different among the different genotype groups (P < 0.05). 4. The present study revealed that the incidence of the CYP2C19*1, *2 and *3 alleles in Chinese Li population is different to that in other ethnic populations of China. There was an obvious relationship between CYP2C19 genotype and omeprazole hydroxylation phenotype, and about 90% of phenotypic PM can be explained by the CYP2C19*2 and *3 alleles.

Genetic polymorphism of cytochrome P450 2C19 in Mexican Americans: A cross-ethnic comparative study

Our objectives were to investigate cytochrome P450 (CYP) 2C19 polymorphism in Mexican Americans and compare the findings with those in 4 other ethnic groups. The CYP2C19 genotype (n = 346) and S-mephenytoin hydroxylation phenotype (n = 220) were studied in a Mexican American population from Los Angeles County. Another 4 ethnic groups, African Americans (n = 236), whites (n = 273), East Asians (n = 161), and Southeast Asians (n = 80), were also recruited from Los Angeles County and genotyped and phenotyped for CYP2C19. The frequencies of CYP2C19*2 and *3 were 9.7% and 0.1%, respectively, in Mexican Americans, which were lower than those of the other 4 ethnic groups, ranging from 12.7% to 31.2% and 0.8% to 9.6%, respectively (P <or= .035). Seven Mexican American subjects were phenotyped as poor metabolizers. Thus the frequency of poor metabolizers in the Mexican American subjects was 3.2% (95% confidence interval, 0%-11.9%), which is similar to that of African Americans (5.4%) and whites (5.0%) and lower than that of East Asians (16.7%; P < .001) and Southeast Asians (23.9%; P < .001). Of the 7 poor metabolizers who were also genotyped, 2 were homozygous for the CYP2C19*2 alleles. CYP2C19*4, *5, *6, *7, and *8 were studied and did not account for the unexplained finding. The number of functional alleles among the extensive metabolizers correlated with the phenotype, suggesting a gene-dosage effect in Mexican Americans. This is the first study to investigate CYP2C19 polymorphism in Mexican Americans. The frequencies of the CYP2C19*2 and *3 alleles in Mexican Americans were found to be significantly lower than in other ethnic groups. This genotypic pattern might be responsible for the lower rate of poor metabolizers in Mexican Americans compared with other ethnic groups.

Sequence-based CYP2D6 Genotyping in the Korean Population

For clinical application of pharmacogenetic tests, quantitative prediction of enzyme activity based on accurate determination of genotype is essential. There has been limited information available on the genetic polymorphism of CYP2D6 in the Korean population. In this study, CYP2D6 genotypes were assessed in 400 Korean subjects. Twenty-eight different CYP2D6 alleles and 35 genotypes were detected. On the basis of the genotype determined, the frequency of poor metabolizers and ultrarapid metabolizers were 0.22% and 1.25%, respectively. The CYP2D6 activity expected in regard to different allele combinations varies widely within the extensive and intermediate metabolizer groups. The frequencies of CYP2D6*10 and CYP2D6*5 were 45.00% and 6.13%, respectively. CYP2D6*10xN was found in 4 out of 9 cases with a CYP2D6 duplication. Fifteen heterozygotes for *41 were noted. In addition, the authors measured plasma concentrations of 16 healthy volunteers after administration of nortriptyline and identified the impact of the CYP2D6 genotype on nortriptyline metabolism. This is the first large-scale study to examine the genetic polymorphism of CYP2D6 using sequence-based genotyping in an Asian population. Our results further the understanding of CYP2D6 pharmacogenetics and could be helpful for future clinical studies in the Asian population.

Development of a Predictive Pharmacokinetic Model for a Novel Cyclooxygenase‐2 Inhibitor

A predictive population pharmacokinetic model was developed for a novel cyclooxygenase-2 (COX-2) inhibitor CS-706, using data from 130 subjects in 3 phase 1 trials after single or multiple doses of CS-706 (2- to 800-mg doses daily, up to 14 days) and validated using sparse data from a separate study. A 2-compartment model described the data. Typical apparent clearance (CL/F) was 47.2 L/h and was reduced by 43% at doses greater than 200 mg. Apparent clearance was decreased by 38% in female subjects and by 64% and 15%, respectively, in poor/intermediate CYP 2D6 and poor CYP 2C9 metabolizers. Typical apparent volume of the central compartment was 166 L and increased with body weight. Bioavailability increased by 42% after nighttime doses and decreased saturably with increasing dose (50% reduction at 221 mg). Predicted exposures in Japanese subjects were reduced relative to whites because of a lower frequency of poor metabolizers. The model may aid in optimizing the design of future studies and predicting exposures in other subpopulations.

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese. The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7--18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; chi(2) test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n=45) (95% CI: 10.8--19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6--5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3-5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7--11.4%) and 5.3% (95% CI: 3.7--7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0--9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses. The frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.

Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population

Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population

Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population

Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population

Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population

To investigate the association between cytochrome P450 2C19 (CYP2C19) gene polymorphism and cancer susceptibility by genotyping of CYP2C19 poor metabolizers (PMs) in cancer patients. One hundred and thirty-five cases of esophagus cancer, 148 cases of stomach cancer, 212 cases of lung cancer, 112 cases of bladder cancer and 372 controls were genotyped by allele specific amplification-polymerase chain reaction (ASA-PCR) for CYP2C19 PMs. The frequencies of PMs in cancer groups and control group were compared. The frequencies of PMs of CYP2C19 were 34.1%(46/135) in the group of esophagus cancer patients, 31.8%(47/148) in the stomach cancer patients, 34.4%(73/212) in the group of lung cancer patients, only 4.5%(5/112) in the bladder cancer patients and 14.0%(52/372) in control group. There were statistical differences between the cancer groups and control group (esophagus cancer, chi(2)=25.65, P<0.005, OR=3.18, 95%CI=2.005-5.042; stomach cancer, chi(2)=21.70, P<0.005, OR=2.86, 95%CI=1.820-4.501; lung cancer, chi(2)=33.58, P<0.005, OR=3.23, 95%CI=1.503-6.906; bladder cancer, chi(2)=7.50, P<0.01, OR=0.288, 95%CI=0.112-0.740). CYP2C19 PMs have a high incidence of esophagus cancer, stomach cancer and lung cancer, conversely they have a low incidence of bladder cancer. It suggests that CYP2C19 may participate in the activation of procarcinogen of esophagus cancer, stomach cancer and lung cancer, but may involve in the detoxification of carcinogens of bladder cancer.

Bioinformatics Research on Inter-racial Difference in Drug Metabolism II. Analysis on Relationship between Enzyme Activities of CYP2D6 and CYP2C19 and their Relevant Genotypes

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. We have analyzed frequencies of mutant alleles and PMs based on the published data in previous study (Shimizu, T. et al.: Bioinformatics research on inter-racial difference in drug metabolism, I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.). The study shows that there were racial differences in the frequencies of each mutant allele and PMs. In the present study, the correlation between genotypes and drug-metabolizing enzyme activities was investigated. The result showed that enzyme activities varied according to the genotypes of subjects even in the same race. On the other hand, if subjects had the same genotypes, almost no racial differences were observed in drug-metabolizing enzyme activities. From these results, it was supposed that the racial differences in activities of these enzymes could be explained by the differences in distribution of genotypes. It would be possible to explain the racial differences in drug-metabolizing enzyme activities based on the differences on individual pharmacogenetic background information, not merely by comparison of frameworks such as races and nations.

Bioinformatics Research on Inter-racial Difference in Drug Metabolism I. Analysis on Frequencies of Mutant Alleles and Poor Metabolizers on CYP2D6 and CYP2C19

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.

CYP2D6 extensive, intermediate, and poor phenotypes and genotypes in a Polish population

This study investigated the distribution of the CYP2D6 genotypes and phenotypes in a Polish population and compared the concordance of the two methods. Six hundred unrelated healthy individuals from southwestern Poland were studied. The CYP2D6 phenotype was analyzed in 300 individuals using sparteine as a model drug. The CYP2D6 genotype was analyzed in 300 individuals by polymerase chain reaction amplification and restriction fragment length polymorphism techniques for the CYP2D6*1, CYP2D6*3, and CYP2D6*4 alleles. Additionally, in 60 randomly selected healthy individuals both the CYP2D6 phenotype and genotype was assessed to determine accordance between the methods. Of 300 participants in the study 25 (8.3%) were classified as poor metabolizers, 44 (14.7%) as intermediate metabolizers, and 231 (77%) as extensive metabolizers of sparteine. The frequency of CYP2D6*1, CYP2D6*3, and CYP2D6*4 alleles among the genotyped 300 persons was 75.7%, 1.3%, and 23.0%, respectively. The frequency of CYP2D6 deficient genotypes in a Polish population (8.0%) was similar to phenotyping results. The comparison of phenotype and genotype in 60 randomly selected individuals showed a good concordance of the obtained results. CONCLUSIONS. The frequencies of poor metabolizers for CYP2D6 phenotype (8.3%) and genotype (8.0%) in a Polish population from the southwestern region are in concordance and compare well with most results of poor oxidation metabolizers in other white populations.