extensive metabolizers
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Author(s):  
Sara Shum ◽  
Aprajita Yadav ◽  
Emily Fay ◽  
Sue Moreni ◽  
Jennie Mao ◽  
...  

Author(s):  
Rulan Griesel ◽  
Gary Maartens ◽  
Maxwell Chirehwa ◽  
Simiso Sokhela ◽  
Godspower Akpomiemie ◽  
...  

Abstract Background Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART). Methods We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm. Results There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.


Author(s):  
Mahnaz Ahmadimanesh ◽  
Mehri Bemani Naeini ◽  
Mohammad-Reza Rouini ◽  
Shahin Shadnia ◽  
Mahmoud Ghazi-Khansari

AbstractObjectivesDue to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured.MethodsA pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated.ResultsFemale cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms.ConclusionsAccording to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.


2019 ◽  
Vol 20 (10) ◽  
pp. 719-729
Author(s):  
Aarthi Manoharan ◽  
Deepak Gopal Shewade ◽  
Pradeep Anand Ravindranath ◽  
Ravi Philip Rajkumar ◽  
Vedam L Ramprasad ◽  
...  

Aim: The CYP2D6 gene is highly polymorphic and harbors population specific alleles that define its predominant metabolizer phenotype. This study aimed to identify polymorphisms in Indian population owing to scarcity of CYP2D6 data in this population. Materials & methods: The CYP2D6 gene was resequenced in 105 south Indians using next generation sequencing technology and haplotypes were reconstructed. Results & conclusion: Four novel missense variants have been designated as CYP2D6*110, *111, *112 and *113. The most common alleles were CYP2D6*1 (42%), *2 (32%), and *41 (12.3%) and diplotypes were CYP2D6*1/*2 (26%), *1/*1 (11%), *2/*41 (10%) and *1/*41 (7%) accounting for high incidence of extensive metabolizers in Indians.


2017 ◽  
Vol 33 (3) ◽  
pp. 277-284 ◽  
Author(s):  
Soichiro Ebisawa ◽  
Yasushi Ueki ◽  
Tomoaki Mochidome ◽  
Keisuke Senda ◽  
Hitoshi Nishimura ◽  
...  

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3962-3962 ◽  
Author(s):  
Claire A McClain ◽  
M Brooke Bernhardt ◽  
Amanda Berger ◽  
Ryan Winslow ◽  
Michael E Scheurer ◽  
...  

Abstract Introduction Vincristine is vital in the treatment of acute lymphoblastic leukemia (ALL), but is dose-limited by the development of disabling neuropathies. Vincristine is metabolized extensively by polymorphically expressed CYP3A4/5, which contributes to its 10-fold inter-patient pharmacokinetic variability. Further, there is more recent evidence that an inherited polymorphism in the CEP72 rs924607 gene contributes to vincristine sensitivity. Hispanic children have among the lowest rates of ALL survival when compared to other ethnicities, and pharmacogenomic variability among races is postulated to contribute. This is the first study to examine specifically both CYP3A5 polymorphisms and CEP72 gene expression in correlation with vincristine neurotoxicity in a large cohort of Hispanic ALL patients. Methods Banked germline blood samples from 300 self-identified Hispanic patients with ALL treated at Texas Children's Hospital between 1990 and 2015 were interrogated for allelic discrimination of CEP72 and at the CYP3A5*3, *6, and *7 polymorphic loci using TaqMan assays. Patient medical records were electronically searched for evidence of neuropathic events. Neuropathies were categorized as motor or sensory and graded using the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies. Missing administered vincristine data was imputed using the patient's known treatment protocol and date of event coupled with protocol specifics retrieved from the literature. Multivariate analysis was run modeling the influences of CYP3A5 and CEP72 genotypes on the development and time to development of greater than or equal to Grade 3 neuropathies. Descriptive statistics were used to identify the prevalence of CYP3A5 and CEP72 genotypes and the associated phenotypes in this patient population. Time to neuropathy analysis was performed using the Kaplan-Meier failure estimates and log-rank test in Stata V.12.1 (College Station, TX). Results Based on CYP3A5 polymorphisms, overall, we found that 5% of our patients were extensive metabolizers of vincristine, 33% were intermediate metabolizers, and 62% were poor metabolizers. Additionally, we found that the TT risk CEP72 genotype is a rare finding in our cohort (9.3%). Clinically, we found that 18.4% of our patients experienced greater than or equal to Grade 3 neurotoxicity. Assessing the influence of being both a CYP3A5 intermediate or poor metabolizer and having the TT risk CEP72 genotype was limited by the paucity of patients with both genotypes (n=25). However, CYP3A5 poor metabolizers experienced neurotoxicity more often than intermediate or extensive metabolizers, although we did not find a statistically significant correlation between phenotype and incidence of neurotoxicity. Additionally, we found that there was a statistically significant difference in time to development of neurotoxicity within the first 100 days of treatment between intermediate and poor CYP3A5 metabolizers (P=0.036), with poor metabolizers experiencing greater than or equal to Grade 3 neurotoxicity sooner (Figure 1). Conclusions For the first time, we show that CYP3A5 poor metabolizers experienced greater than or equal to Grade 3 neurotoxicity significantly sooner than intermediate metabolizers within the first 100 days of treatment. We found a low prevalence of the minor allele of CEP72 rs924607TT in our Hispanic cohort. However, classification of CYP3A5 metabolizers and genotypes within our Hispanic population as well as our incidence of neurotoxicity are consistent with current literature. Further testing in a larger cohort should be performed but this study reinforces the significance of CYP3A5 metabolism of vincristine in leading to significant neurotoxicity and suggests that, at least in Hispanic patients, vigilance to early development of neurotoxicity should be performed by practitioners. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


2015 ◽  
Vol 71 (12) ◽  
pp. 1467-1475
Author(s):  
Takuma Kagami ◽  
Mitsushige Sugimoto ◽  
Hitomi Ichikawa ◽  
Shu Sahara ◽  
Takahiro Uotani ◽  
...  

2015 ◽  
Vol 88 (4) ◽  
pp. 513-520 ◽  
Author(s):  
Ioana Todor ◽  
Adina Popa ◽  
Maria Neag ◽  
Dana Muntean ◽  
Corina Bocsan ◽  
...  

Background and aims. To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers.Methods. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine  and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period.Results. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively.Conclusions. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.


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