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Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children.

ABSTRACT: Aim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results: CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion: We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV.

SUBMITTER: Packiasabapathy S

PROVIDER: S-EPMC8238023 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children.

Packiasabapathy Senthil S Aruldhas Blessed W BW Zhang Pengyue P Overholser Brian R BR Quinney Sara K SK Sadhasivam Senthilkumar S

Pharmacogenomics 20210608 10

Aim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadon ...[more]

PMID: 34100292

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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.

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.

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Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children.

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Novel associations between <i>CYP2B6</i> polymorphisms, perioperative methadone metabolism and clinical outcomes in children.

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