Pharmacogenetics and genomics最新文献

{"title":"Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis.","authors":"Ying Zhang,&nbsp;Xu Hao,&nbsp;Kelu Hou,&nbsp;Lei Hu,&nbsp;Jingyuan Shang,&nbsp;Shiyu He,&nbsp;Changqing Yang,&nbsp;Lin Huang,&nbsp;Yufei Feng","doi":"10.1097/FPC.0000000000000470","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000470","url":null,"abstract":"<p><strong>Objective: </strong>To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole.</p><p><strong>Methods: </strong>We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity.</p><p><strong>Results: </strong>A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03-1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06-1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35-3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23-2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94-2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity.</p><p><strong>Conclusion: </strong>IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":" ","pages":"257-267"},"PeriodicalIF":2.6,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40682758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of pharmacologic interactions between omeprazole and tacrolimus in a membranous nephropathy patient with CYP3A5 nonexpresser: a case report.","authors":"Yanli Li,&nbsp;Yi Liu,&nbsp;Zengxian Sun","doi":"10.1097/FPC.0000000000000478","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000478","url":null,"abstract":"<p><p>Tacrolimus has been widely used in membranous nephropathy in recent years. The drug interactions of the coadministration of tacrolimus with omeprazole in CYP3A5 nonexpresser membranous nephropathy patients have not been demonstrated. Here, we report an idiopathic membranous nephropathy patient who was with CYP2C19*2/*2, CYP3A5*3/*3 (nonexpresser) and ABCB1 (3435 TT, 1236 computed tomography, 2677 TT) genotype requiring treatment with tacrolimus and omeprazole and found to have fluctuating metabolism of tacrolimus. This study shows that tacrolimus and omeprazole have pharmacologic drug interactions in CYP3A5 nonexpressers, implying that the CYP3A and ABCB1 gene mutations linked to tacrolimus metabolism may alter tacrolimus levels in the blood. The observed concentrations of tacrolimus were decreased after the discontinuation of omeprazole therapy. It demonstrates that, in addition to genotype, clinical covariates, such as omeprazole are important when it comes to better understanding and prediction of tacrolimus dosage. It is deemed necessary to monitor tacrolimus blood concentrations and make dose adjustments when patients were coadministered with omeprazole.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 7","pages":"268-271"},"PeriodicalIF":2.6,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10582991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis.","authors":"Qinghong Dai,&nbsp;Xuyang Xia,&nbsp;Chenjia He,&nbsp;Yupeng Huang,&nbsp;Yidan Chen,&nbsp;Yang Wu,&nbsp;Yuehong Chen,&nbsp;Qianqian Hou,&nbsp;Yang Shu,&nbsp;Wei Zhang,&nbsp;Heng Xu,&nbsp;Geng Yin,&nbsp;Qibing Xie","doi":"10.1097/FPC.0000000000000468","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000468","url":null,"abstract":"<p><strong>Objective: </strong>Gut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria.</p><p><strong>Methods: </strong>Fecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis.</p><p><strong>Results: </strong>Significantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium ) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor  = -0.52, P  = 8 × 10 -5 for Megamonsa ). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity.</p><p><strong>Conclusions: </strong>Microbiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 7","pages":"247-256"},"PeriodicalIF":2.6,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/da/0d/pgen-32-247.PMC9351697.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10225607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer genomic medicine in Japan and the roles of pharmacists.","authors":"Tohru Aomori,&nbsp;Hiroomi Sakurai,&nbsp;Hiroshi Nishihara","doi":"10.1097/FPC.0000000000000476","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000476","url":null,"abstract":"<p><p>Cancer genomic medicine (CGM) is a medical service that provides optimized treatment for each patient based on genes, biomarkers, environment, and lifestyle. In Japan, the approval of designed core hospitals for CGM started in 2017. In June 2019, two types of cancer gene panel tests became available in the national health insurance system, and CGM was socially implemented. While CGM is still in its infancy and there are some issues that need to be resolved, there are cases where the treatment has shown dramatic results. The present review highlights the CGM system in Japan, the issues it faces, and the role of pharmacists in this system.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 6","pages":"242-245"},"PeriodicalIF":2.6,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10543655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenetic analysis of canonical versus noncanonical pathway of NF-kB in Crohn's disease patients under anti-tumor necrosis factor-α treatment.","authors":"Eleana F Stavrou,&nbsp;Fani Chatzopoulou,&nbsp;Charalabos Antonatos,&nbsp;Panagiota Pappa,&nbsp;Eutychia Makridou,&nbsp;Konstantinos Oikonomou,&nbsp;Andreas Kapsoritakis,&nbsp;Petros S Potamianos,&nbsp;Konstantinos Karmiris,&nbsp;Charalambos Tzathas,&nbsp;Dimitris Chatzidimitriou,&nbsp;Ioannis S Vizirianakis,&nbsp;Yiannis Vasilopoulos","doi":"10.1097/FPC.0000000000000471","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000471","url":null,"abstract":"<p><strong>Objectives: </strong>This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients.</p><p><strong>Materials and methods: </strong>A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment.</p><p><strong>Results: </strong>Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073).</p><p><strong>Conclusion: </strong>Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 6","pages":"235-241"},"PeriodicalIF":2.6,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10193081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide DNA methylation profile of peripheral blood lymphocytes from subjects with nonsteroidal anti-inflammatory drug-induced respiratory diseases.","authors":"Jong-Uk Lee,&nbsp;Hun Soo Chang,&nbsp;Min Kyung Kim,&nbsp;Seung-Lee Park,&nbsp;Jung Hyun Kim,&nbsp;Jong-Sook Park,&nbsp;Choon-Sik Park","doi":"10.1097/FPC.0000000000000475","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000475","url":null,"abstract":"<p><strong>Background: </strong>Significant changes in CpG methylation have been identified in nasal polyps, which are the main targets of nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD); however, these polyps are composed of various cellular components. In the present study, whole-genome CpG methylation in peripheral blood lymphocytes (PBLs) was analyzed to define the epigenetic changes in lymphocytes, which are the primary immune cells involved in NERD.</p><p><strong>Materials and methods: </strong>Genomic DNA from peripheral blood mononuclear cells from 27 NERD and 24 aspirin-tolerant asthma (ATA) was subjected to bisulfate conversion and a methylation array. Quantitative CpG methylation, the β-values as a quantitative measure of DNA methylation, in lymphocytes were calculated after adjustments for cellular composition.</p><p><strong>Results: </strong>Fifty-six hypermethylated and three hypomethylated differentially methylated CpGs (DMCs) in PBLs in the NERD compared with ATA. The top 10 CpG loci predicted the methylation risk score, with a positive predictive value of 91.3%, a negative predictive value of 81.5% and an accuracy of 84.3%. As demonstrated in the nasal polyps, 30 DMCs were predicted to bind to the following 10 transcription factors, ranked in descending order: AP-2alphaA, TFII-1, STAT4, FOXP3, GR, c-Est-1, E2F-1, XBP1, ENKTF-1 and NF-1. Gene ontology analysis identified 13 categories such as regulation of T-helper 17 cell differentiation, including SMAD7 and NFKBIZ. PBLs in NERD contained no DMCs in genes associated with the prostaglandin and leukotriene pathways, which were found in ATA.</p><p><strong>Conclusion: </strong>PBLs in NERD form a unique pattern of DNA CpG methylation, and the combined analysis may provide predictive values for NERD.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 6","pages":"226-234"},"PeriodicalIF":2.6,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10543653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of CYP2B6 and CYP3A4 polymorphisms on the virologic and immunologic responses of patients treated with efavirenz-containing regimen.","authors":"Yaya Kassogue, Brehima Diakite, Mamoudou Maiga, Oumar Kassogue, Issa Konate, Kadidiatou Tamboura, Fousseyni Diarra, Zoumana Diarra, Mahamadou Karamoko Sawadogo, Yaya Goita, Sidi Boula Sissoko, Adama Seydou Sissoko, Nouhoum Guirou, Hind Dehbi, Sellama Nadifi, Sekou Bah, Cheick Bougadari Traore, Bakarou Kamate, Sounkalo Dao, Guimogo Dolo","doi":"10.1097/FPC.0000000000000477","DOIUrl":"10.1097/FPC.0000000000000477","url":null,"abstract":"<p><strong>Objectives: </strong>The main objective of this study was to evaluate the effect of CYP2B6 and CYP3A4 polymorphisms on the virological and immunologic responses of HIV patients. A total of 153 HIV-positive patients were enlisted for the study.</p><p><strong>Patients and methods: </strong>Viral load and median CD4 T cell counts were evaluated at baseline and month 6 (M6). Samples were identified using TaqMan genotyping assays.</p><p><strong>Results: </strong>The AG in CYP2B6 rs2279343 was associated with VLS compared to homozygous AA. In the dominant model, the AG/GG genotypes were associated with VLS compared to the AA genotype. Moreover, in overdominant model, the AG genotype was associated with VLS compared to AA/GG. Regarding immunological response, only the AG in SNP rs2279343 CYP2B6 was associated with an increase in CD4 cell count between baseline and M6. In CYP2B6 rs3745274, the CD4 cell count at M6 was higher than that of baseline for GG carriers and for GT carriers. In CYP3A4 rs2740574, the TC carriers showed a higher median CD4 count at M6 compared to that of the baseline count, as well as for CC carriers. The best genotypes combination associated with CD4 cell count improvement were AA/AG in SNP rs2279343 and GG/GT in SNP rs3745274.</p><p><strong>Conclusion: </strong>Our findings support the fact that CYP2B6 rs2279343 could help in the prediction of VLS and both SNPs rs3745274 and rs2279343 in CYP2B6 and CYP3A4 rs2740574 were associated with immune recovery in Malian HIV-positive patients.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 6","pages":"219-225"},"PeriodicalIF":1.7,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613628/pdf/EMS146401.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10193084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proposals for a standardized procedure of validation of DNA extraction and allelic discrimination assays in pharmacogenomics according to ISO15189 requirements.","authors":"Laurent Imbert,&nbsp;Jennifer Lagoutte-Renosi,&nbsp;Julien Wils,&nbsp;Fabien Lamoureux","doi":"10.1097/FPC.0000000000000473","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000473","url":null,"abstract":"<p><strong>Objectives: </strong>In the era of quality management in clinical laboratories, method validation can be a challenge without appropriate guidelines, such as in the field of pharmacogenetics. The present work describes a method validation for DNA extraction and CYP3A5*3 genotyping, which would meet ISO15189:2012 requirements.</p><p><strong>Methods: </strong>DNA extraction was performed using a QIAamp DSP DNA Blood kit, DNA purity and concentration were determined using a Nanodrop, and the genotyping assay was a real-rime PCR using TaqMan reagents. Validation criteria were similar to those usually verified when validating methods in the analytical field: specificity, sensitivity, cross-over contamination, stability of reagents, robustness, lower and upper limits of detection, and between-run and within-run precisions. A comparison to alternate or reference methods was also performed (i.e. QiAamp kit versus DNA extractor and TaqMan genotyping versus Sanger sequencing). Each validation step is described from the pharmacogenetic point of view, as well as acceptance criteria for both DNA extraction [i.e. concentration relative SD (RSD) below 25%, verified purity, and no DNA in blank samples] and genotyping assay (i.e. specificity and diagnostic sensitivity, RSD of mean threshold cycle below 15%, no amplification in blank samples).</p><p><strong>Results: </strong>Concerning CYP3A5 genotyping following a DNA extraction described as an example, validation criteria were met, allowing routine use of this analytical process. Cost estimation of the overall validation procedure was approximately 290 euros, concerning reagents and consumables.</p><p><strong>Conclusion: </strong>This work aims to provide a reference for method validation for pharmacogenetic analysis using real-time PCR to detect single nucleotide polymorphisms, in accordance with ISO15189:2012.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"192-200"},"PeriodicalIF":2.6,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10247759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population genetic polymorphisms of pharmacogenes in Zimbabwe, a potential guide for the safe and efficacious use of medicines in people of African ancestry.","authors":"Bianza T Mbavha,&nbsp;Comfort R Kanji,&nbsp;Nadina Stadler,&nbsp;Julia Stingl,&nbsp;Andrea Stanglmair,&nbsp;Catharina Scholl,&nbsp;William Wekwete,&nbsp;Collen Masimirembwa","doi":"10.1097/FPC.0000000000000467","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000467","url":null,"abstract":"<p><strong>Objective: </strong>Pharmacogenomics (PGx) is a clinically significant factor in the safe and efficacious use of medicines. While PGx knowledge is abundant for other populations, there are scarce PGx data on African populations and is little knowledge on drug-gene interactions for medicines used to treat diseases common in Africa. The aim of this study was to use a custom-designed open array to genotype clinically actionable variants in a Zimbabwean population. This study also identified some of the commonly used drugs in Zimbabwe and the associated genes involved in their metabolism.</p><p><strong>Methods: </strong>A custom-designed open array that covers 120 genetic variants was used to genotype 522 black Zimbabwean healthy volunteers using TaqMan-based single nucleotide polymorphism genotyping. Data were also accessed from Essential Drugs' List in Zimbabwe (EDLIZ), and the medicines were grouped into the associated biomarker groups based on their metabolism. We also estimated the national drug procurement levels for medicines that could benefit from PGx-guided use based on the data obtained from the national authorities in Zimbabwe.</p><p><strong>Results: </strong>The results demonstrate the applicability of an open-array chip in simultaneously determining multiple genetic variants in an individual, thus significantly reducing cost and time to generate PGx data. There were significantly high frequencies of African-specific variants, such as the CYP2D6*17 and *29 variants and the CYP2B6*18 variant. The data obtained showed that the Zimbabwean population exhibits PGx variations in genes important for the safe and efficacious use of drugs approved by the EDLIZ and are procured at significantly large amounts annually. The study has established a cohort of genotyped healthy volunteers that can be accessed and used in the conduct of clinical pharmacogenetic studies for drugs entering a market of people of predominantly African ancestry.</p><p><strong>Conclusion: </strong>Our study demonstrated the potential benefit of integrating PGx in Zimbabwe for the safe and efficacious use of drugs that are commonly used.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"173-182"},"PeriodicalIF":2.6,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10194579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients.","authors":"Michelle Liu, Ciara M Shaver, Kelly A Birdwell, Stephanie A Heeney, Christian M Shaffer, Sara L Van Driest","doi":"10.1097/FPC.0000000000000472","DOIUrl":"10.1097/FPC.0000000000000472","url":null,"abstract":"<p><strong>Objectives: </strong>Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D).</p><p><strong>Methods: </strong>We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed.</p><p><strong>Results: </strong>Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (P = 0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 (interquartile range: 147.6-267.5) (ng/ml)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), P = 0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes.</p><p><strong>Conclusion: </strong>These data indicate that a composite CYP3A phenotype incorporating both increase and decrease variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"209-217"},"PeriodicalIF":1.7,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177686/pdf/nihms-1788678.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}