cyp2d6 activity
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2021 ◽  
Vol 12 ◽  
Author(s):  
Alexandra G. A. Stewart ◽  
Peter A. Zimmerman ◽  
James S. McCarthy

Primaquine, an 8-aminoquinoline, is the only medication approved by the World Health Organization to treat the hypnozoite stage of Plasmodium vivax and P. ovale malaria. Relapse, triggered by activation of dormant hypnozoites in the liver, can occur weeks to years after primary infection, and provides the predominant source of transmission in endemic settings. Hence, primaquine is essential for individual treatment and P. vivax elimination efforts. However, primaquine use is limited by the risk of life-threatening acute hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. More recently, studies have demonstrated decreased efficacy of primaquine due to cytochrome P450 2D6 (CYP2D6) polymorphisms conferring an impaired metabolizer phenotype. Failure of standard primaquine therapy has occurred in individuals with decreased or absent CYP2D6 activity. Both G6PD and CYP2D6 are highly polymorphic genes, with considerable geographic and interethnic variability, adding complexity to primaquine use. Innovative strategies are required to overcome the dual challenge of G6PD deficiency and impaired primaquine metabolism. Further understanding of the pharmacogenetics of primaquine is key to utilizing its full potential. Accurate CYP2D6 genotype-phenotype translation may optimize primaquine dosing strategies for impaired metabolizers and expand its use in a safe, efficacious manner. At an individual level the current challenges with G6PD diagnostics and CYP2D6 testing limit clinical implementation of pharmacogenetics. However, further characterisation of the overlap and spectrum of G6PD and CYP2D6 activity may optimize primaquine use at a population level and facilitate region-specific dosing strategies for mass drug administration. This precision public health approach merits further investigation for P. vivax elimination.


Author(s):  
Jean C Dinh ◽  
Erin C Boone ◽  
Vincent S Staggs ◽  
Robin E Pearce ◽  
Wendy Y Wang ◽  
...  

Author(s):  
Linda Thorén ◽  
Mikael Eriksson ◽  
Jonatan D. Lindh ◽  
Kamila Czene ◽  
Jonas Bergh ◽  
...  

Abstract Purpose Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. Methods Swedish breast cancer patients (n = 699)  operated 2006–2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. Results Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. Conclusion Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Guiming Hu ◽  
Fei Gao ◽  
Guanzhe Wang ◽  
Yan Fang ◽  
Yuanyuan Guo ◽  
...  

Abstract Background Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. Methods Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. Results We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. Conclusions The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC.


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Anielle de Pina-Costa ◽  
Ana Carolina Rios Silvino ◽  
Edwiges Motta dos Santos ◽  
Renata Saraiva Pedro ◽  
José Moreira ◽  
...  

Abstract Background The relapsing nature of Plasmodium vivax infection is a major barrier to its control and elimination. Factors such as adequate dosing, adherence, drug quality, and pharmacogenetics can impact the effectiveness of radical cure of P. vivax and need to be adequately evaluated. CYP2D6 pathway mediates the activation of primaquine (primaquine) into an active metabolite(s) in hepatocytes, and impaired activity has been linked to a higher risk of relapse. Cases presentation Three patients diagnosed with P. vivax malaria presented repeated relapses after being initially treated with chloroquine (25 mg/kg) and primaquine (3.5 mg/kg in 14 days) at a non-endemic travel clinic. Recurring episodes were subsequently treated with a higher dose of primaquine (7 mg/kg in 14 days), which prevented further relapses in two patients. However, one patient still presented two episodes after a higher primaquine dose and was prescribed 300 mg of chloroquine weekly to prevent further episodes. Impaired CYP2D6 function was observed in all of them. Conclusion Lack of response to primaquine was associated with impaired CYP2D6 activity in three patients presenting multiple relapses followed in a non-endemic setting. Higher primaquine dosage was safe and effectively prevented relapses in two patients and should be further investigated as an option in Latin America. It is crucial to investigate the factors associated with unsuccessful radical cures and alternative therapeutic options.


Author(s):  
Gaëlle Magliocco ◽  
Jules Desmeules ◽  
Alain Matthey ◽  
Luis M. Quirós‐Guerrero ◽  
Nasim Bararpour ◽  
...  
Keyword(s):  

Author(s):  
Mo'tasem Mohamed Alsmadi ◽  
Laith Naser AL-Eitan ◽  
Nasir Mohammed Idkaidek ◽  
Karem Hasan Alzoubi

Background: Atomoxetine is a treatment for attention-deficit hyperactivity disorder. It inhibits norepinephrine transporters (NET) in the brain. Renal impairment can reduce hepatic CYP2D6 activity and atomoxetine elimination which may increase its body exposure. Atomoxetine can be secreted in saliva. Objective: The objective of this work was to test the hypothesis that atomoxetine saliva levels (sATX) can be used to predict ATX brain extracellular fluid (bECF) levels and their pharmacological effects in healthy subjects and those with end-stage renal disease (ESRD). Methods: The pharmacokinetics of atomoxetine after intravenous administration to rats with chemically induced acute and chronic renal impairments were investigated. A physiologically-based pharmacokinetic (PBPK) model was built and verified in rats using previously published measured atomoxetine levels in plasma and brain tissue. The rat PBPK model was then scaled to humans and verified using published measured atomoxetine levels in plasma, saliva, and bECF. Results: The rat PBPK model predicted the observed reduced atomoxetine clearance due to renal impairment in rats. The PBPK model predicted atomoxetine exposure in human plasma, sATX, and bECF. Additionally, it predicted that ATX bECF levels needed to inhibit NET are achieved at 80 mg dose. In ESRD patients, the developed PBPK model predicted that the previously reported 65% increase in plasma exposure in these patients could be associated with a 63% increase in bECF. The PBPK simulations showed that there is a significant correlation between sATX and bECF in humans. Conclusion: Saliva levels can be used to predict atomoxetine pharmacological response.


2021 ◽  
Vol 12 ◽  
Author(s):  
Katja S. Just ◽  
Harald Dormann ◽  
Mathias Freitag ◽  
Marlen Schurig ◽  
Miriam Böhme ◽  
...  

Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample (n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01–1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00–1.60]). The composed CYP2D6 activity was positively associated with dizziness (p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.


2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
VA Shumkov ◽  
KA Zagorodnikova ◽  
SA Boldueva ◽  
VB Petrova

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Bisoprolol is one of the most effective and frequently prescribed beta-blockers. The widespread use of bisoprolol is due to its high efficiency in the treatment of patients with various cardiological pathologies: arterial hypertension, ischemic heart disease, chronic heart failure. Bisoprolol, like all members of the group of beta-adrenergic blockers, is effective in the treatment of patients with acute myocardial infarction, reducing the risk of complications such as rhythm disturbances and sudden cardiac death. In vitro studies indicate that bisoprolol is a substrate for two isoforms of cytochrome P450 - 3A4 and 2D6. Purpose The purpose of this work was to analyze the effect of CYP2D6 activity on the chronotropic effect of bisoprolol therapy in patients with acute coronary syndrome (ACS). Materials and methods The study included patients with ACS who was assigned bisoprolol according to clinical indications. All patients included in the study were Holter monitor on the 10th day of hospitalization - the minimum, mean, maximum heart rate during the day and the maximum heart rate were assessed at the time of exercise was evaluated against the background of the current therapy. All patients included in the study also underwent molecular genetic testing. The detection of polymorphic variants of СYP2D6 (*3/*4) gene was carried out by real-time PCR. Results A total of 93 patients, 58 males and 35 females were included in the study. The average age of patients is 63 years.  In the studied population, CYP2D6 * 3 was not detected. The CYP2D6 * 4 mutation occurred with a frequency of 15%, which is comparable to previously published data on the Russian population. The distribution of alleles corresponded to the Hardy-Weinberg law (Chi square, p> 0.05). In order to determine the effect of genetically determined CYP2D6 activity on the effectiveness of bisoprolol therapy in patients with ACS, we identified a group of patients - carriers of the allelic CYP2D6 * 4 variant in homozygous or heterozygous form (AA / AG) (group with a reduced metabolic rate), and a group with the CYP2D6 genotype GG (group with normal and increased metabolic rate). In the correlation analysis, carriage of CYP2D6 * 4 in heterozygous or homozygous form was associated with a lower maximum heart rate during exercise (r-0.21; p <0.05). Maximum heart rate during exercise in carriers of CYP2D6 * 4 was 107 [105; 119], in the comparison group - 114 [108; 120]. The difference was significant with p <0.05 (values are expressed as median [25%; 75%]). Conclusion In this study, for the first time, the role of the influence of allelic variants of the CYP2D6 gene on the achievement of maximum heart rate during exercise was revealed when using bisoprolol in patients with ACS. These data may have promising implications for maximizing the personalization of therapy for patients, including those with ACS.


2021 ◽  
Vol 12 ◽  
Author(s):  
Rajeev K. Mehlotra ◽  
Andrea Gaedigk ◽  
Rosalind E. Howes ◽  
Tovonahary A. Rakotomanga ◽  
Arsene C. Ratsimbasoa ◽  
...  

Plasmodium vivax is one of the five human malaria parasite species, which has a wide geographical distribution and can cause severe disease and fatal outcomes. It has the ability to relapse from dormant liver stages (hypnozoites), weeks to months after clearance of the acute blood-stage infection. An 8-aminoquinoline drug primaquine (PQ) can clear the hypnozoites, and thus can be used as an anti-relapse therapeutic agent. Recently, a number of studies have found that its efficacy is compromised by polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene; decreased or absence of CYP2D6 activity contributes to PQ therapeutic failure. The present study sought to characterize CYP2D6 genetic variation in Madagascar, where populations originated from admixture between Asian and African populations, vivax malaria is endemic, and PQ can be deployed soon to achieve national malaria elimination. In a total of 211 samples collected from two health districts, CYP2D6 decreased function alleles CYP2D6*10, *17, *29, *36+*10, and *41 were observed at frequencies of 3.55–17.06%. In addition, nonfunctional alleles were observed, the most common of which were CYP2D6*4 (2.13%), *5 (1.66%), and the *4x2 gene duplication (1.42%). Given these frequencies, 34.6% of the individuals were predicted to be intermediate metabolizers (IM) with an enzyme activity score (AS) ≤ 1.0; both the IM phenotype and AS ≤ 1.0 have been found to be associated with PQ therapeutic failure. Furthermore, the allele and genotype frequency distributions add to the archaeological and genomic evidence of Malagasy populations constituting a unique, Asian-African admixed origin. The results from this exploratory study provide fresh insights about genomic characteristics that could affect the metabolism of PQ into its active state, and may enable optimization of PQ treatment across human genetic diversity, which is critical for achieving P. vivax elimination.


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