Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children.
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SUBMITTER: Packiasabapathy S
PROVIDER: S-EPMC8238023 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundInterindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism.MethodsHealthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry.ResultsAverage S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1 homozygotes and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism.ConclusionsCYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.
| S-EPMC4667947 | biostudies-literature
Project description:ObjectiveAlthough the quality of perioperative sleep is gaining increasing attention in clinical recovery, its impact role remains unknown and may deserve further exploration. This study aimed to investigate the associations between perioperative sleep patterns and clinical outcomes among patients with intracranial tumors.MethodsA correlation study was conducted in patients with intracranial tumors. Perioperative sleep patterns were assessed using a dedicated sleep monitor for 6 consecutive days. Clinical outcomes were gained through medical records and follow-up. Spearman's correlation coefficient and multiple linear regression analysis were applied to evaluate the associations between perioperative sleep patterns and clinical outcomes.ResultsOf 110 patients, 48 (43.6%) were men, with a median age of 57 years. A total of 618 days of data on perioperative sleep patterns were collected and analyzed. Multiple linear regression models revealed that the preoperative blood glucose was positively related to the preoperative frequency of awakenings (β = 0.125; 95% CI = 0.029-0.221; P = 0.011). The level of post-operative nausea and vomiting was negatively related to perioperative deep sleep time (β = -0.015; 95% CI = -0.027--0.003; P = 0.015). The level of anxiety and depression was negatively related to perioperative deep sleep time, respectively (β = -0.048; 95% CI = -0.089-0.008; P = 0.020, β = -0.041; 95% CI = -0.076-0.006; P = 0.021). The comprehensive complication index was positively related to the perioperative frequency of awakenings (β = 3.075; 95% CI = 1.080-5.070; P = 0.003). The post-operative length of stay was negatively related to perioperative deep sleep time (β = -0.067; 95% CI = -0.113-0.021; P = 0.005). The Pittsburgh Sleep Quality Index was positively related to perioperative sleep onset latency (β = 0.097; 95% CI = 0.044-0.150; P < 0.001) and negatively related to perioperative deep sleep time (β = -0.079; 95% CI = -0.122-0.035; P < 0.001).ConclusionPerioperative sleep patterns are associated with different clinical outcomes. Poor perioperative sleep quality, especially reduced deep sleep time, has a negative impact on clinical outcomes. Clinicians should, therefore, pay more attention to sleep quality and improve it during the perioperative period.Clinical trial registrationhttp://www.chictr.org.cn, identifier: ChiCTR2200059425.
| S-EPMC10508910 | biostudies-literature
Project description:The aim of this study was to determine the influence of ABCB1, CYP2B6, and CYP3A4 genetic polymorphisms on methadone metabolism in patients with hepatitis C virus (HCV) undergoing methadone maintenance treatment (MMT). The study included 35 participants undergoing MMT, who were divided in three groups: HCV-positive (N=12), HCV-negative (N=16), and HCV clinical remission (CR) (N=7). The concentrations of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were determined with gas chromatography-mass spectrometry. The patients were genotyped for ABCB1 rs1045642, CYP2B6 rs3745274, CYP3A4 rs2242480, and CYP3A4 rs2740574 polymorphisms. Differences between single nucleotide polymorphism (SNP) genotypes and methadone-to-EDDP ratio were analysed with one-way ANOVA, which showed no significant difference between the genes (p=0.3772 for ABCB1 rs1045642, p=0.6909 for CYP2B6 rs3745274, and p=0.6533 for CYP3A4 rs2242480). None of the four analysed SNP genotypes correlated with methadone-to-EDDP concentration ratio. A major influence on it in hepatitis C-positive patients turned out to be the stage of liver damage.
| S-EPMC7968507 | biostudies-literature
Project description:BackgroundMethadone therapy is a major protocol in opioid addiction cases in many health care systems. Population-based studies have shown that in addicted people, the genetic profile affects their response to methadone therapy. Therefore, this study designed to examine the frequency of two SNPs of the CYP2B6 gene (rs3745274 and rs3211371) in addicted cases in two methadone-responders and methadone non-responders groups.MethodsA total of 199 opioid-addicted individuals and 117 unaffected control subjects were genotyped for rs3745274 and rs3211371 polymorphisms of the CYP2B6 gene using the tetra-primer amplification refractory mutation system-polymerase chain reaction.ResultsResults of this study revealed the significant association of rs3745274 GG (p < 0.001; OR = 0.027; 95% CI = 0.14-0.49) and GT (p < 0.001; OR = 4.04; 95% CI = 2.26-7.21) genotypes with the risk of addiction in methadone-responders. Also, a significant association between rs3745274 GG (p < 0.001; OR = 0.28; 95% CI = 0.15-0.51) and GT (p < 0.001; OR = 5.1; 95% CI = 2.8-5.28) genotypes and addiction relapse was found in methadone non-responders.ConclusionBased on our findings, we can conclude that rs3745274 variant of CYP2B6 gene could serve as a potential biomarker, to evaluate the prognosis of addicted people fate under treatment with methadone.
| S-EPMC8183388 | biostudies-literature
Project description:Polymorphisms in CYP2B6 affect the steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, a single dose of nevirapine has been widely prescribed to pregnant women at delivery, to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). We characterized associations between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz.Plasma drug concentrations were determined over the 13-day period after administration of a 200-mg oral dose of nevirapine to nonpregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered, and pharmacokinetic sampling was repeated. Pharmacokinetic parameters were estimated using a noncompartmental approach. Primary analyses involved 2 CYP2B6 polymorphisms (516G --> T and 983T --> C) known to predict increased steady-state plasma nevirapine and efavirenz exposure. Exploratory analyses involved another 51 polymorphisms in CYP2B6, ABCB1, CYP3A4, and CYP3A5.On the basis of the composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. The composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and the pharmacokinetics of nevirapine and efavirenz.Selective pressure for drug-resistant HIV-1 after administration of single-dose nevirapine may not differ substantially according to CYP2B6 516/983 genotype. Additional polymorphisms, genes, and populations warrant further study.
| S-EPMC2784690 | biostudies-literature
Project description:BackgroundGenetic variability may influence methadone metabolism, dose requirements, and risk of relapse.ObjectivesTo determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment).MethodsTwo independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms.ResultsWe screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05-1.00, p = 0.03) with minimal heterogeneity (I(2) = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27-2.61, p = 0.02) however significant heterogeneity was observed (I(2) = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response.ConclusionAlthough the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.
| S-EPMC3906028 | biostudies-literature
Project description:AimsMethadone metabolism and clearance are determined principally by polymorphic cytochrome P4502B6 (CYP2B6). Some CYP2B6 allelic variants affect methadone metabolism in vitro and disposition in vivo. We assessed methadone metabolism by CYP2B6 minor variants in vitro. We also assessed the influence of CYP2B6 variants, and P450 oxidoreductase (POR) and CYP2C19 variants, on methadone clearance in surgical patients in vivo.MethodsCYP2B6 and P450 oxidoreductase variants were coexpressed with cytochrome b5 . The metabolism of methadone racemate and enantiomers was measured at therapeutic concentrations and intrinsic clearances were determined. Adolescents receiving methadone for surgery were genotyped for CYP2B6, CYP2C19 and POR, and methadone clearance and metabolite formation clearance were determined.ResultsIn vitro, CYP2B6.4 was more active than wild-type CYP2B6.1. CYPs 2B6.5, 2B6.6, 2B6.7, 2B6.9, 2B6.17, 2B6.19 and 2B6.26 were less active. CYPs 2B6.16 and 2B6.18 were inactive. CYP2B6.1 expressed with POR variants POR.28, POR.5 and P228L had lower rates of methadone metabolism than wild-type reductase. In vivo, methadone clinical clearance decreased linearly with the number of CYP2B6 slow metabolizer alleles, but was not different in CYP2C19 slow or rapid metabolizer phenotypes, or in carriers of the POR*28 allele.ConclusionsSeveral CYP2B6 and POR variants were slow metabolizers of methadone in vitro. Polymorphisms in CYP2B6, but not CYP2C19 or P450 reductase, affected methadone clearance in vivo. CYP2B6 polymorphisms 516G>T and 983T>C code for canonical loss of function variants and should be assessed when considering genetic influences on clinical methadone disposition. These complementary translational in vitro and in vivo results inform on pharmacogenetic variability affecting methadone disposition in patients.
| S-EPMC10908252 | biostudies-literature
Project description:BackgroundH19 polymorphisms have been reported to correlate with an increased susceptibility to a few types of cancers, although their role in neuroblastoma has not yet been clarified.Materials and methods We investigated the association between three single polymorphisms (rs2839698 G>A, rs3024270 C>G, and rs217727 G>A) and neuroblastoma susceptibility in Chinese Han populations. Three hundred ninety-three neuroblastoma patients and 812 healthy controls were enrolled from the Henan and Guangdong provinces. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to determine the strength of the association of interest.Results Separated and combined analyses revealed no associations of the rs2839698 G>A, rs3024270 C>G or rs217727 G>A polymorphisms and neuroblastoma susceptibility. In the stratification analysis, female children with rs3024270 GG genotypes had an increased neuroblastoma risk (adjusted OR = 1.61, 95% CI = 1.04-2.50, P=0.032).Conclusion The rs3024270 GG genotype might contribute to an increased neuroblastoma susceptibility in female Chinese children.
| S-EPMC6449514 | biostudies-literature
Project description:BACKGROUND:The arachidonic acid (AA) pathway is suspected to be involved in the development of various cancers, including prostate cancer. However, the role of single nucleotide polymorphisms (SNPs) of AA pathway genes remains unclear. The purpose of this case-control study was to evaluate the association between prostate cancer risk and 14 such SNPs in the PTGS2, PTGES2, ALOX5, ALOX5AP, and LTA4H genes. METHODS:Genotyping was conducted on 585 white prostate cancer cases and 585 healthy, age-matched controls. The best genetic model for each SNP was determined using Akaike's information criterion. Odds ratios for the association between each SNP and prostate cancer risk were calculated, both overall and stratified by obesity (BMI???30). Haplotype analysis was conducted for the PTGES2 SNPs. RESULTS:LTA4H rs1978331 was inversely associated with prostate cancer risk overall (unadjusted, overdominant model OR?=?0.68, 95% CI: 0.51-0.91 for TC vs. TT/CC). Among non-obese individuals, the GG genotype of PTGES2 rs10987883 was associated with an increased risk for prostate cancer (unadjusted, recessive model OR?=?3.23, 95% CI: 1.27-8.23). CONCLUSIONS:Our results indicate that SNPs in certain AA metabolism genes may influence prostate cancer susceptibility. Furthermore, it is possible that obesity, which induces a chronic state of low-level inflammation in addition to several metabolic sequelae, may modify the impact of these SNPs. These findings should be confirmed in a larger study with power to detect differential effects by obesity.
| S-EPMC7339922 | biostudies-literature
Project description:BackgroundHirschsprung's disease (HSCR) is an enteric nervous system birth defect partially caused by a genetic disorder. Single-nucleotide polymorphisms (SNPs) of the cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene are reported to be associated with HSCR.MethodsWe evaluated the association of rs2054675, rs707265, and rs1042389 with HSCR susceptibility in southern Chinese children including 1470 HSCR patients and 1473 controls using the TaqMan SNP Genotyping Assay.Resultsrs2054675 C allele and the rs707265 G allele were risk SNPs for total colonic aganglionosis (OR = 1.82, 95% CI 1.29 ~ 2.55, P_adj < 0.001 and OR = 0.68, 95% CI 0.48 ~ 0.97, P_adj = 0.034). These results suggested that CYP2B6 rs2054675 and rs707265 polymorphisms were associated with increased susceptibility to the severe HSCR subtype in southern Chinese children.ConclusionWe suggest that CYP2B6 rs2054675 and rs707265 polymorphisms are associated with increased susceptibility to the severe HSCR subtype in southern Chinese children.
| S-EPMC8649360 | biostudies-literature