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

Shimizu, Takako; Ochiai, Haruka; Åsell, Fredrik; Yokono, Yoshiya; Kikuchi, Yoshiharu; Nitta, Masashi; Hama, Yoshimasa; Yamaguchi, Shizuyo; Hashimoto, Munehiro; Taki, Katsuhiko; Nakata, Kotoko; Aida, Yoshitaka; Ohashi, Akiyoshi; Ozawa, Naok̆i

doi:10.2133/dmpk.18.71

Cited by 21 publications

(12 citation statements)

References 63 publications

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“…We also did not evaluate CYP2C19 status, where poor metabolizers have been shown to have lower VPCs (12,30). The frequency of poor CYP2C19 metabolizers was reported to be significantly higher in Asians (15% to 20%) than in Caucasians (2% to 3%), and in this study, none of the included patients was of Asian origin (31). Further, some previously described factors, such as concomitant PPI treatment, were present in the vast majority of included patients, while other factors, such as concomitant phenytoin or rifampin medication, were present in very few.…”

Section: Discussionmentioning

confidence: 77%

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

Hoenigl

Duettmann

Raggam

et al. 2013

Antimicrob Agents Chemother

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Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment.

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Section: Discussionmentioning

confidence: 77%

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

Hoenigl

Duettmann

Raggam

et al. 2013

Antimicrob Agents Chemother

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“…Genetic polymorphism and phenotypic studies have shown that PMs account for approximately 7.7% among Caucasians, but only approximately 1% among Asians . IMs are mainly distributed in Asian populations; for example, CYP2D6*10, a common gene mutation in Chinese individuals, has a frequency as high as 64%‐70% . In contrast, in Caucasians, CYP2D6 IM has a population frequency of <0.5% .…”

Section: What Is Known and Objectivementioning

confidence: 99%

Association between aripiprazole pharmacokinetics and CYP2D6 phenotypes: A systematic review and meta-analysis

et al. 2018

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Summary What is known and objective The FDA has provided recommendations for aripiprazole use in CYP2D6 poor metabolizers (PMs); however, PMs make up <1% of the Asian population and no recommendation has been provided for intermediate metabolizers (IMs), who comprise a considerable proportion of the Asian population (64%‐70% occurrence of CYP2D6*10). This study aimed to investigate the characteristics of aripiprazole metabolism in IMs and other phenotypes by conducting the first meta‐analysis of the association among CYP2D6 phenotypes and aripiprazole pharmacokinetics (PK). Methods We searched four electronic databases for studies published through February 2018, investigating the association between aripiprazole and CYP2D6 gene polymorphisms. Gene polymorphism information was extracted, and CYP2D6 phenotypes were determined according to a unified classification standard. The associations between three aripiprazole PK‐related outcomes and CYP2D6 phenotype were analysed. Meta‐analyses were used to compare ultra‐rapid metabolizers (UMs) vs extensive metabolizers (EMs), EMs vs IMs and IMs vs poor metabolizers (PMs) for each outcome. The aripiprazole serum concentration funnel plot and the Egger's and Begg's tests were used to assess publication bias. Results and discussion Altogether, 10 studies were included in this analysis (n = 649). Aripiprazole serum concentration differed significantly between EMs and IMs (EM vs IM pooled SMD: −0.383; 95% CI: −0.735 to −0.031, P = 0.03 < 0.05), but not between IMs and PMs (IM vs PM pooled SMD: −0.425; 95% CI: −0.933 to 0.082, P = 0.10 > 0.05). However, aripiprazole plus dehydroaripiprazole serum level did not significantly differ among EMs, IMs and PMs (EM vs IM pooled SMD: −0.285; 95% CI: −0.724 to 0.154, P = 0.20 > 0.05; IM vs PM pooled SMD: −0.302; 95%CI: −0.810 to 0.205, P = 0.24 > 0.05). Overall, aripiprazole serum level and the sum level of aripiprazole plus dehydroaripiprazole in different phenotypes followed the trend UMs < EMs < IMs < PMs, whereas dehydroaripiprazole serum level followed the trend UMs < EMs > IMs > PMs. What is new and conclusion Aripiprazole serum concentration differed significantly between EMs and IMs, but not between PMs. Whether this has clinical significance requires further evaluation by randomized trials.

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“…In addition, carriers of reduced activity alleles are termed intermediate metabolizers (IM) and exhibit a rate of metabolism between that of EM and PM, and ultrarapid metabolizers (UM) usually carry multiple copies of functional alleles and produce excess enzymatic activity. These four main phenotypes occur with varying prevalence in populations of different ethnic or geographic origin [2][3][4] .…”

mentioning

confidence: 99%

Data-Mining Methods as Useful Tools for Predicting Individual Drug Response: Application to <i>CYP2D6</i> Data

Sabbagh

Darlu

2006

Hum Hered

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Objectives: Selecting a maximally informative subset of polymorphisms to predict a clinical outcome, such as drug response, requires appropriate search methods due to the increased dimensionality associated with looking at multiple genotypes. In this study, we investigated the ability of several pattern recognition methods to identify the most informative markers in the CYP2D6 gene for the prediction of CYP2D6 metabolizer status. Methods: Four data-mining tools were explored: decision trees, random forests, artificial neural networks, and the multifactor dimensionality reduction (MDR) method. Marker selection was performed separately in eight population samples of different ethnic origin to evaluate to what extent the most informative markers differ across ethnic groups. Results: Our results show that the number of polymorphisms required to predict CYP2D6 metabolic phenotype with a high accuracy can be dramatically reduced owing to the strong haplotype block structure observed at CYP2D6. MDR and neural networks provided nearly identical results and performed the best. Conclusion: Data-mining methods, such as MDR and neural networks, appear as promising tools to improve the efficiency of genotyping tests in pharmacogenetics with the ultimate goal of pre-screening patients for individual therapy selection with minimum genotyping effort.

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

Cited by 21 publications

References 63 publications

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

Potential Factors for Inadequate Voriconazole Plasma Concentrations in Intensive Care Unit Patients and Patients with Hematological Malignancies

Association between aripiprazole pharmacokinetics and CYP2D6 phenotypes: A systematic review and meta-analysis

Data-Mining Methods as Useful Tools for Predicting Individual Drug Response: Application to <i>CYP2D6</i> Data

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