Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

AbstractRecently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the CYP2D6*10 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for CYP2D6*10 as recommended, and the revised phenotype groupings improve the relationship between CYP2D6 genotype and risperidone measures. One hundred and ninety-nine children and adolescents with autism treated with a risperidone-based regimen for at least four weeks were included. CYP2D6 genotype was determined using the Luminex xTAG CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of risperidone, risperidone concentration/dose ratio, and risperidone/9-hydroxyrisperidone ratio in patients with an activity score < 1 were significantly higher than those ≥ 1 (P value < 0.001 for all three parameters). Plasma risperidone levels and risperidone concentration/dose ratios were significantly higher in intermediate metabolizers (defined as AS = 0.25–0.75) than normal metabolizer (defined as AS = 1–2) patients (1.44 vs. 0.23 ng/ml, P < 0.001 and 1.63 vs. 0.29 ng/ml/ng, P < 0.001, respectively) as well as risperidone/9-hydroxyrisperidone ratio (0.20 vs. 0.04, P < 0.001). This is the first study in an Asian population utilizing the revised CPIC-recommended method for translating the CYP2D6 genotype to phenotype. In addition to validating that CYP2D6 genetic variation significantly impacts risperidone metabolism, we demonstrated that revised value for the CYP2D6*10 was superior for genotype to phenotype translation. However, at least for risperidone, subjects with an activity score of 1 presented as phenotypic normal, and not intermediate metabolizers, suggesting that phenotype classification is substrate dependent.

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Gene Polymorphisms and Their Association to Coronavirus Family Infections: Susceptibility in Different Populations

Medical & Clinical Research ◽

10.33140/mcr.05.012 ◽

2020 ◽

Vol 5 ◽

Keyword(s):

Genetic Variants ◽

Viral Infections ◽

Human Leukocyte ◽

Asian Population ◽

African Region ◽

Mediterranean Populations ◽

Susceptibility To Infection ◽

Asian Populations ◽

Spread Pattern ◽

Different Populations

Human leukocyte antigen (HLA) loci are highly polymorphic and determine differential features of the immune response in subjects from different regions. HLA genes have been proposed to determine genetic susceptibility to several diseases, particularly to viral infections. Moreover, it has been suggested that each ethnic group could have a different specificity of T-lymphocyte reactivity to the same viral infections. In this review, we analyzed the distribution of HLA types in countries of the Asian, European and North African region. Also, we studied the relation between these HLA polymorphisms and susceptibility to infection by the coronavirus. Our findings indicated that homozygosity would increase susceptibility to viral infections and, in some cases, to coronavirus infection. HLA types showing higher susceptibility were reported in Asian population, including China, Singapore, and Taiwan. In contrast, lower susceptibility HLA variants were detected among African populations, some Asian populations, and Mediterranean populations. The presented evidence along with the spread pattern of COVID-19 infection suggests that HLA genetic variants might be related to its infection susceptibility and severity. The investigation of HLA genetic variants distribution would be a useful tool to predict different populations’ susceptibility to viral infections.

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PARP1 rs1136410 Val762Ala contributes to an increased risk of overall cancer in the East Asian population: a meta-analysis

Journal of International Medical Research ◽

10.1177/0300060521992956 ◽

2021 ◽

Vol 49 (3) ◽

pp. 030006052199295

Author(s):

Yijuan Xin ◽

Liu Yang ◽

Mingquan Su ◽

Xiaoli Cheng ◽

Lin Zhu ◽

...

Keyword(s):

Cancer Risk ◽

Odds Ratio ◽

Chinese Population ◽

Meta Analysis ◽

Asian Population ◽

Cancer Type ◽

East Asians ◽

Asian Populations ◽

Increased Risk ◽

Meta Analyses

Objectives To investigate the association between poly(ADP-ribose) polymerase 1 ( PARP1) rs1136410 Val762Ala and cancer risk in Asian populations, as published findings remain controversial. Methods The PubMed and EMBASE databases were searched, and references of identified studies and reviews were screened, to find relevant studies. Meta-analyses were performed to evaluate the association between PARP1 rs1136410 Val762Ala and cancer risk, reported as odds ratio (OR) and 95% confidence interval (CI). Results A total of 24 studies with 8 926 cases and 15 295 controls were included. Overall, a significant association was found between PARP1 rs1136410 Val762Ala and cancer risk in East Asians (homozygous: OR 1.19, 95% CI 1.06, 1.35; heterozygous: OR 1.10, 95% CI 1.04, 1.17; recessive: OR 1.13, 95% CI 1.02, 1.25; dominant: OR 1.13, 95% CI 1.06, 1.19; and allele comparison: OR 1.09, 95% CI 1.03, 1.15). Stratification analyses by race and cancer type revealed similar results for gastric cancer among the Chinese population. Conclusion The findings suggest that PARP1 rs1136410 Val762Ala may be significantly associated with an increased cancer risk in Asians, particularly the Chinese population.

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Comparison of the Genetic Structure of Rheumatoid Arthritis Between European and Asian Population

10.21203/rs.3.rs-642514/v1 ◽

2021 ◽

Author(s):

Chun'e Li ◽

Xiaomeng Chu ◽

Shiqiang Cheng ◽

Yan Wen ◽

Chuyu Pan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Genetic Structure ◽

Genome Wide Association Study ◽

Inflammatory Diseases ◽

Enrichment Analysis ◽

Asian Population ◽

Arginine Deiminase ◽

Gene Set Enrichment Analysis ◽

Asian Populations ◽

Shared Risk

Abstract Background: Rheumatoid arthritis (RA) is one of the chronic inflammatory diseases that primarily influences the joints, and its prevalence is 0.5-1.0%. Previous studies have shown that there are differences in the genetic structure of RA between European and Asian populations, and most of the studies have been conducted using meta-analysis. This study analyzed the genetic structure of rheumatoid arthritis in European and Asian populations using a new method. Methods: The Genome-Wide Association Study (GWAS) summary statistics of RA from Europe (N=8383) and Asia (N=19190) were derived from an article published in Nature. First, the GWAS data was divided into 1368 blocks, in which SNPs were approximately independent of linkage disequilibrium (LD). Second, we calculated the LD matrix of SNP in each block by using PLINK 1.9. Then, PESCA analysis was performed to detect population-specific/shared risk genes of RA. Finally, Metascape platform was used to perform gene set enrichment analysis. Results: In European population, we found multiple genes which were associated with RA, including HLA-DPA1, HLA-DPB1 (rs2856822, PTP=1.000), MICA (rs2844518, PTP=1.000). In Asian population, C6orf10 (rs3129915, PTP=1.000), PTPN2 (rs2847288, PTP=0.995), were significant related to RA. The population-shared genes included PADI2 (rs2235920, PTP=1.000), STAT4 (rs12612769, PTP=1.000). Furthermore, gene sets enrichment analysis reported population-specific/shared pathway terms, such as interferon-gamma-mediated signaling pathway (P=2.884×10-9), negative regulation of innate immune response (P=1.841×10-7), protein-arginine deiminase activity (P=7.047×10-8). Conclusions: The results of our study indicate differences in risk loci between Asian and European populations, which provided clues for exploring the population-specific/shared genetics and pathogenesis of RA.

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Genetic Analysis of LRRK2 R1628P in Parkinson’s Disease in Asian Populations

Parkinson s Disease ◽

10.1155/2017/8093124 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Yuan Zhang ◽

Qiying Sun ◽

Minhan Yi ◽

Xun Zhou ◽

Jifeng Guo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Risk Factor ◽

Chinese Population ◽

Genetic Factors ◽

Meta Analysis ◽

Asian Population ◽

High Quality ◽

Asian Populations ◽

Risk Variants

Although the etiology of Parkinson’s disease (PD) remains unclear, there is increasing evidence of genetic factors contributing to the onset of PD. Various mutations and risk variants of the gene LRRK2 have been reported, but the association between LRRK2 R1628P and PD is still inconsistent. Thus, we conducted a meta-analysis to determine the potential relationship between R1628P and PD. Our study sample was an aggregate of 17 publications, which in total consisted of 9,275 PD patients and 8,114 controls. All of these articles are of high quality according to NOS, and there was no obvious reporting bias or heterogeneity. In a general Asian population, the pooled OR of the risk genotype contrasts was 1.83 (95% CI: 1.57, 2.13). When stratified by ethnicity, the pooled ORs were 1.84 (95% CI: 1.56, 2.18) in a Chinese population and 1.79 (95% CI: 1.27, 2.52) in a non-Chinese population. Our study suggests that LRRK2 R1628P appears to be a risk factor for PD in Asian populations, both Chinese and non-Chinese.

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Managing hypertension in 2018: which guideline to follow?

Heart Asia ◽

10.1136/heartasia-2018-011127 ◽

2019 ◽

Vol 11 (1) ◽

pp. e011127 ◽

Cited By ~ 5

Author(s):

Fabio Angeli ◽

Gianpaolo Reboldi ◽

Monica Trapasso ◽

Adolfo Aita ◽

Paolo Verdecchia

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Low Income ◽

Asian Population ◽

Public Health Issue ◽

Global Public Health ◽

Asian Countries ◽

Western Countries ◽

Asian Populations ◽

The Impact

Hypertension is a global public health issue and a major cause of morbidity and mortality. Its prevalence is increasing in many Asian countries, with a number of countries with blood pressure above the global average. Although the average systolic blood pressure is decreasing worldwide since the 1980s at the rate of about 1 mm Hg systolic blood pressure per decade, it is increasing in low-income and middle-income countries, especially in the East and South Asian population. Of note, the much larger base Asian population results in a considerably larger absolute number of individuals affected. When compared with Western countries, hypertension among Asian populations has unique features in terms of its onset, clustering of associated cardiovascular risk factors, complications and outcomes. Moreover, only a minority of hypertensive individuals are receiving treatment and achieving control. Projected number of deaths related to hypertension dramatically increased in the last 25 years in some Asian regions with a disproportionately high mortality and morbidity from stroke compared with Western countries. The relation between blood pressure and the risk of stroke is stronger in Asia than in Western regions. Although new Guidelines for hypertension diagnosis and management have been recently released from Europe and North America, the unique features of Asian hypertensive patients raise concerns on the clinical applicability of Western Guidelines to Asian populations. To this purpose, we critically reviewed key elements from the most updated Guidelines. We also discussed their core concepts to verify the impact on hypertension prevention and management in Asian countries.

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Association between body mass index (BMI) and hypertension in south Asian population: evidence from nationally-representative surveys

Clinical Hypertension ◽

10.1186/s40885-019-0134-8 ◽

2019 ◽

Vol 25 (1) ◽

Cited By ~ 3

Author(s):

Fariha Binte Hossain ◽

Gourab Adhikary ◽

Ariful Bari Chowdhury ◽

Md Shajedur Rahman Shawon

Keyword(s):

Body Mass Index ◽

Body Mass ◽

South Asian ◽

Asian Population ◽

Wealth Index ◽

Population Level ◽

Overweight And Obesity ◽

National Committee ◽

South Asian Population ◽

Asian Populations

Abstract Background Although there has been a well-established association between overweight-obesity and hypertension, whether such associations are heterogeneous for South Asian populations, or for different socioeconomic groups is not well-known. We explored the associations of overweight and obesity using South Asian cut-offs with hypertension, and also examined the relationships between body mass index (BMI) and hypertension in various socioeconomic subgroups. Methods We analysed the recent Demographic and Health Survey (DHS) data from Bangladesh, India, and Nepal, with a total of 821,040 men and women. Hypertension was defined by 2017 ACC/AHA cut-offs and by Joint National Committee 7 (JNC7) cut-offs for measured blood pressure and overweight and obesity were defined by measured height and weight. We used multiple logistic regressions to estimate the odds ratios (ORs) with 95% confidence intervals (CIs) of hypertension for overweight and obesity as well as for each 5-unit increase in BMI. Results The prevalence of hypertension using JNC7 cut-offs among participants increased by age in all three countries. The prevalence ranged from 17.4% in 35–44 years to 34.9% in ≥55 years in Bangladesh, from 4.6% in 18–24 years to 28.6% in 45–54 years in India, and from 3.8% in 18–24 years to 39.2% in ≥55 years in Nepal. Men were more likely to be hypertensive than women in India and Nepal, but not in Bangladesh. Overweight and obesity using both WHO and South Asian cut-offs were associated with higher odds of hypertension in all countries. For each 5 kg/m2 increase in BMI, the ORs for hypertension were 1.79 (95% CI: 1.65–1.93), 1.59 (95% CI: 1.58–1.61), and 2.03 (95% CI: 1.90–2.16) in Bangladesh, India, and Nepal, respectively. The associations between BMI and hypertension were consistent across various subgroups defined by sex, age, urbanicity, educational attainment and household’s wealth index. Conclusions Our study shows that the association of BMI with hypertension is stronger for South Asian populations at even lower cut-offs points for overweight and obesity. Therefore, public health measures to reduce population-level reduction in BMI in all population groups would also help in lowering the burden of hypertension.

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Allo-Immunity to Erythrocytes in Relation to Blood Transfusion and Pregnancy: Cooperative Study of Allo-Immunity to Antigen Diversity in Asian Populations.

Blood ◽

10.1182/blood.v114.22.3144.3144 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3144-3144

Author(s):

Akihiro Takeshita ◽

Hiroko Watanabe ◽

Dae Won Kim ◽

Kyou Sup Han ◽

So Yong Kwon ◽

...

Keyword(s):

Hong Kong ◽

Blood Transfusion ◽

Conflicts Of Interest ◽

Collaborative Study ◽

Asian Population ◽

Screening Methods ◽

Blood Transfusions ◽

Cooperative Study ◽

Asian Populations ◽

The World

Abstract Abstract 3144 Poster Board III-81 Purpose Allo-immunization to erythrocytes is an important issue with regard to blood transfusions, albeit perhaps less prominent than other possible adverse effects. Several studies including pregnant and transfused cases have been conducted in US and European counties. However, a sufficient international or interracial comparative study has not been performed yet. Asian populations contain a wide variety of genetics and circumstances. They may differ in immune responses to allo-antigens that are common among American and European populations. Because no confirmed nor detail information exists for many Asian populations, collaborative international study concerning these issues will improve blood transfusions and transplantations not only in Asia but also the world. (Method) Forty-eight institutes, including those in Japan (29), Korea (15), Hong Kong (1), Singapore (1), Malaysia (1) and Thailand (1), participated in this first cooperative study of Asian population examining allo-immunity to erythrocytes. The total number of independent cases included more than 866,000 patients. Ab screening methods adopted in these institutes included gel columns, beads columns, traditional tubes or some combination of these three. If a case was tested multiple times, we counted it as one case. Multiple antibodies detected during the study in one patient were separately analyzed. Patients with unconfirmed histories were excluded from the study. We analyzed and compared the frequencies of irregular antibodies (Abs) to erythrocyte antigens between patients of different gender, patients pregnant or not, and patients with and without previous blood transfusion. Results Abs were determined in 8,880 patients (male /female: 3,528 /5,482), including 1801 /2418 from Japan, 946 /1477 from Korea, 287 /688 from Malaysia, 214 /408 from Thailand, 237 /375 from Hong Kong, and 11 /15 from Singapore. Of note, anti-D Ab was more frequently detected in females (p<0.01), but varies among countries as follows; 0.6 /2.4 (male /female, %) in Japan, 1.7 /8.1 in Korea, and 8.0 /19.6 in Malaysia. It significantly increased in pregnant patients (4.8% in Japan, 35.9% in Korea, 34.0% in Malaysia), but did not increase in patients that had received blood transfusion. Other Abs including complex ones did not significantly increase in pregnant patients. Anti-D Ab was rare in other Asian counties. Anti-E Ab was 1.4 times more frequently detected in patients that had received blood transfusion. [Japan (2.4x), Thailand (3.1x) Hong Kong (1.3x) and Singapore (1.3x)]. Anti-Jka and -C Abs increased in patients that had received blood transfusion. Anti-Dia Ab increased 1.6 times more in Japan, but did not in Korea (0.5x). Anti-c+E complex Abs, increased in patients that had received blood transfusion in many Asian counties. However, other complex Abs such as Anti-Lea+Leb Abs did not. Conclusion Although there have been several previous reports on allo-immunity in pregnant and transfused cases, this is the first international collaborative study in allo-immunity to erythrocyte antigens in relation to gender, pregnancy and blood transfusion status in Asia. Anti-D Ab was frequently detected in pregnant female patients. Anti-E, -Jka and -C Abs were frequently detected in patients that had received blood transfusion. However, the frequency varies among Asian countries. These data will contribute to the international body of knowledge concerning allo-immunity, allowing for advancements in successful blood transfusion in Asia and the world. The number of cases might be small in the light of total Asian populations, therefore, we should continue and spread the study. Disclosures No relevant conflicts of interest to declare.

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CYP2D6 genotypes in association with steady state plasma concentrations of active metabolites of tamoxifen in patients with breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.634 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 634-634 ◽

Cited By ~ 1

Author(s):

H. Lim ◽

H. Lee ◽

K. Lee ◽

E. Lee ◽

I. Jang ◽

...

Keyword(s):

Breast Cancer ◽

Steady State ◽

Plasma Concentrations ◽

Cancer Center ◽

Cyp2d6 Genotype ◽

Active Metabolites ◽

Fluorescence Detector ◽

Wilcoxon Rank Sum Test ◽

Center Hospital ◽

State Plasma

634 Background: Tamoxifen is a prodrug that is metabolized to active metabolites, Z-4-hydroxy-N-desmethyltamoxifen (BX) and Z-4-hydroxy-tamoxifen (4OH) where CYP2D6 plays a major role in the conversion. Genetic polymorphisms of CYP2D6 by ethnicities are well known with CYP2D6*10 in Asians (up to 50% in Koreans), and CYP2D6 *2 and *4 in American Whites as major variant alleles. We analyzed the steady state plasma concentrations of tamoxifen and its metabolites in patients (pts) with breast cancer to evaluate their associations with various CYP2D6 genotypes. Methods: Blood samples were collected from 219 pts on tamoxifen, 20 mg daily as adjuvant therapy for more than 3 months at National Cancer Center, Korea. Plasma tamoxifen, N-desmethyltamoxifen, BX, 4OH were measured by validated HPLC with fluorescence detector, and analyzed according to CYP2D6 genotype groups by Wilcoxon rank sum test. CYP2D6*10, CYP2D6*5 and CYP2D6*2×2 were identified by PCR-RFLP methods, and the rests were classified as CYP2D6*1 (wild type). This study was approved by IRB at National Cancer Center Hospital (NCCNHS04–033) and conducted after informed consent obtained by the patients. Results: Thus far, we measured plasma concentration of tamoxifen and its metabolites for 158 pts among 198 pts genotyped. 59 pts (29.8%) carried CYP2D6*1/*1, 84 pts (42.4%) *1/*10 and 49 pts (24.7%) *10/*10. Other types were CYP2D6*1/*5 (8.6%), *5/*5 (1.0%), *1/*2×2 (2.5%). Pts with CYP2D6 *10/*10 (n=40) demonstrated significantly lower steady state plasma concentrations of BX and 4OH than those with other genotypes (n=118) (BX: 7.9 vs.19.2. ng/ml [95 % CI; 5.5–10.4 vs. 15.8–22.7 ng/ml] p<0.0001; 4OH: 1.5 vs. 2.8 ng/ml [95 % CI; 1.1–2.0 vs. 2.3–3.3 ng/ml] p<0.0001), whereas there were no differences with *1/*10 (n=64) vs. without *10 allele (n=54) (BX: 20.6 vs. 18.1 ng/ml; 4OH: 2.9 vs. 2.7 ng/ml). Basically no significant differences in BX/4OH or other compounds by various CYP2D6*2 ×2 and *5 alleles were observed. Conclusions: The steady state plasma concentrations of BX and 4OH were significantly low with CYP2D6 *10/*10 genotype, and their clinical implications need to be explored.(Supported by a grant NCC-0410590). No significant financial relationships to disclose.

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Gabapentin and Pregabalin Can Interact Synergistically with Naproxen to Produce Antihyperalgesia

Anesthesiology ◽

10.1097/00000542-200211000-00033 ◽

2002 ◽

Vol 97 (5) ◽

pp. 1263-1273 ◽

Cited By ~ 105

Author(s):

Robert W. Hurley ◽

Debika Chatterjea ◽

Meihua Rose Feng ◽

Charles P. Taylor ◽

Donna L. Hammond

Keyword(s):

Mass Spectroscopy ◽

Plasma Concentrations ◽

Thermal Hyperalgesia ◽

Radiant Heat ◽

Fixed Dose ◽

Peripheral Inflammation ◽

Additive Effects ◽

Paw Edema ◽

Dose Ratio ◽

Intraplantar Injection

Background Gabapentin and pregabalin are anticonvulsants with antihyperalgesic effects in animal models of neuropathic and inflammatory nociception. This study characterized the manner in which gabapentin or pregabalin interacts with naproxen to suppress thermal hyperalgesia and inflammation in the carrageenan model of peripheral inflammation. Methods Gabapentin, pregabalin, naproxen, or a fixed-dose ratio of gabapentin + naproxen or pregabalin + naproxen was administered orally to rats after the induction of inflammation by intraplantar injection of lambda-carrageenan in one hind paw. Nociceptive thresholds were determined by the radiant heat paw-withdrawal test. Paw edema was measured by plethysmometry. Drug plasma concentrations were determined by a liquid chromatography-mass spectroscopy-mass spectroscopy method. Results Gabapentin, pregabalin, and naproxen alone reversed thermal hyperalgesia with ED50 values of 19.2, 6.0, and 0.5 mg/kg, respectively. Mixtures of gabapentin + naproxen in fixed-dose ratios of 50:1, 10:1, or 1:1 interacted synergistically to reverse carrageenan-induced thermal hyperalgesia. However, 1:50 gabapentin + naproxen produced only additive effects. No combination of gabapentin + naproxen decreased paw edema in a manner greater than additive. Plasma concentrations of gabapentin and naproxen were unaltered by the addition of the other drug. The mixture of 10:1 of pregabalin + naproxen interacted synergistically to reverse thermal hyperalgesia on the inflamed hind paw, whereas mixtures of 1:1 or 1:10 produced additive effects. Conclusions These data suggest that gabapentin + naproxen and pregabalin + naproxen can interact synergistically or additively to reverse thermal hyperalgesia associated with peripheral inflammation. Therefore, the use of gabapentin or pregabalin in low-dose combinations with naproxen may afford therapeutic advantages for clinical treatment of persistent inflammatory pain.

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Ten Years’ Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics

Journal of Personalized Medicine ◽

10.3390/jpm8020015 ◽

2018 ◽

Vol 8 (2) ◽

pp. 15 ◽

Cited By ~ 47

Author(s):

Andrea Gaedigk ◽

Jean Dinh ◽

Hyunyoung Jeong ◽

Bhagwat Prasad ◽

J. Leeder

Keyword(s):

Drug Therapy ◽

Enzymatic Activity ◽

Activity Score ◽

Cyp2d6 Genotype ◽

Cyp2d6 Gene ◽

Seminal Paper ◽

Cyp2d6 Activity ◽

Drug Pair ◽

The Core ◽

Precision Therapeutics

The seminal paper on the CYP2D6 Activity Score (AS) was first published ten years ago and, since its introduction in 2008, it has been widely accepted in the field of pharmacogenetics. This scoring system facilitates the translation of highly complex CYP2D6 diplotype data into a patient’s phenotype to guide drug therapy and is at the core of all CYP2D6 gene/drug pair guidelines issued by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The AS, however, only explains a portion of the variability observed among individuals and ethnicities. In this review, we provide an overview of sources in addition to CYP2D6 genotype that contribute to the variability in CYP2D6-mediated drug metabolism and discuss other factors, genetic and non-genetic, that likely contribute to the observed variability in CYP2D6 enzymatic activity.

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