Exploration of CYP450 and Drug Transporter Genotypes and Correlations with Nevirapine Exposure in Malawians

Brown, Kevin C.; Hosseinipour, Mina C.; Hoskins, Janelle M.; Thirumaran, Ranjit K.; Tien, Hsiao-Chuan; Weigel, Ralf; Tauzie, Jean; Shumba, Ida; Lamba, Jatinder K.; Schuetz, Erin G.; McLeod, Howard L.; Kashuba, Angela D. M.; Corbett, Amanda

doi:10.2217/pgs.11.132

Cited by 25 publications

(20 citation statements)

References 28 publications

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“…In this study, the frequency of CYP2D6*4 1934G/ A polymorphism in healthy controls was comparable with that of published literature by (30). However, it was dissimilar with studies done by (28,29,42,43) (Table S1). CYP2D6*4 1934G/A polymorphism was not associated with susceptibility to ARV-associated hepatotoxicity.…”

Section: Discussionsupporting

confidence: 82%

Prevalence ofCYP2D6*4 1934G/A polymorphism in Western IndianHIVpatients

Singh

Lata

Gangakhedkar

2018

APMIS

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Hepatic CYP2D6 enzyme metabolizes antiretroviral drugs (ARVs) including nevirapine. Polymorphism in CYP2D6 gene affects drug metabolism and displays distinctive phenotypes in the population. Hence, we investigated the prevalence of CYP2D6*4 1934G/A polymorphism in a total of 165 HIV patients that include 34 with and 131 without hepatotoxicity and 160 unrelated healthy controls by the PCR‐RFLP method. The prevalence of CYP2D6*4 1934AA genotype was higher in total HIV patients as compared to healthy controls (1.81% vs 0.6%, OR = 2.86). Similarly, CYP2D6*4 1934AA genotype was much more prevalent in HIV patients without hepatotoxicity as compared to healthy controls (2.3% vs 0.6%, OR = 2.87). Likewise, CYP2D6*4 1934AA genotype was predominant in advanced HIV disease stage as compared to healthy controls (3.8% vs 0.6%, OR = 6.15). CYP2D6*4 1934GA genotype was distributed higher in HIV patients taking tobacco and nevirapine as compared to non‐users (23.3% vs 19.3%, OR = 1.21, 21.0% vs 16.7%, OR = 1.2). Likewise, CYP2D6*4 1934GA genotype was overrepresented in patients with hepatotoxicity taking alcohol + nevirapine as compared to alcohol non‐users + nevirapine users (20.00% vs 16.67%, OR = 1.25). Thus, there was no significant difference in genotype or allele frequencies of CYP2D6*4 1934G/A polymorphism between the patients with hepatotoxicity and those without or healthy controls.

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Section: Discussionsupporting

confidence: 82%

Prevalence ofCYP2D6*4 1934G/A polymorphism in Western IndianHIVpatients

Singh

Lata

Gangakhedkar

2018

APMIS

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“…It is suggested to perform nevirapine plasma concentration monitoring as methadone may influence the efficacy of treatment because it causes a decrease in nevirapine concentrations. Elevated AST levels, age, and weight are identified factors contributing to a high interindividual variance of nevirapine (12,14,(16)(17)(18)(19). In our study, univariate analysis showed that the AST and ALT levels were significantly associated with nevirapine concentrations and AUC 0-12 h. Furthermore, multivariate analyses confirmed that increased ALT levels significantly increased nevirapine concentrations and AUC 0-12 h. A recent study reported that hepatotoxicity was significantly associated with higher nevirapine trough concentrations (20).…”

Section: Discussionsupporting

confidence: 77%

Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

et al. 2016

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Background/aim: Nevirapine is a reverse-transcriptase inhibitor widely used in combination therapy to treat HIV infection. Nevirapine is extensively metabolized in the liver and CYP2B6 is mainly responsible for oxidation of 3-hydroxynevirapine (3-OH NVP). This study aims to explore CYP2B6 activity by measuring 2-hydroxynevirapine (2-OH NVP) and 3-OH NVP in plasma and to identify factors associated with nevirapine pharmacokinetic parameters. Materials and methods:A total of 112 patients were recruited and treated with nevirapine-based antiretroviral therapy. Plasma nevirapine and metabolite concentrations were assayed using high-performance liquid chromatography via liquid-liquid extraction.Results: Thirty-nine (34.8%) of the patients had no 3-OH NVP detected in their plasma while 2-OH NVP was detected in all patients. Metabolite concentrations were low compared to nevirapine. Positive correlations were observed between nevirapine and its metabolites, 2-OH NVP (P < 0.01) and 3-OH NVP (P = 0.012). Nevirapine concentration was decreased when concomitantly administered with methadone. Univariate analysis showed that ALT level, AST level, and detection of 3-OH NVP were associated with nevirapine pharmacokinetic parameters. Conclusion:The variability of nevirapine pharmacokinetic parameters was caused by liver enzymes and the presence of 3-OH NVP metabolites. The presence of 3-OH NVP can probably be used to distinguished CYP2B6 activity and efficacy of nevirapine in patients with HIV infection.

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“…Thus, the existence of a different immunogenetic basis for NVP toxicity in different populations cannot be excluded. Likewise, NVP bioactivation, namely via CYP450-mediated formation of reactive metabolites, can vary among ethnic groups (Stöhr et al, 2008;Wyen et al, 2008;Brown et al, 2012). In view of the evidence, it is reasonable to assume that NVPinduced adverse reactions will depend upon the ability of reactive NVP metabolites to interact with self-proteins involved in the immune response, yielding covalent adducts.…”

Section: Discussionmentioning

confidence: 99%

Evidence for nevirapine bioactivation in man: Searching for the first step in the mechanism of nevirapine toxicity

Caixas¹,

Antunes²,

Marinho³

et al. 2012

Toxicology

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a b s t r a c tDespite its efficacy, including in the prevention of vertical transmission, the antiretroviral nevirapine is associated with severe idiosyncratic hepatotoxicity and skin rash. The mechanisms underlying nevirapine toxicity are not fully understood, but drug bioactivation to reactive metabolites capable of forming stable protein adducts is thought to be involved. This hypothesis is based on the paradigm that drug reactive metabolites have the potential to bind to self-proteins, which results in drug-modified proteins being perceived as foreign by the immune system. The aim of the present work was to identify hemoglobin adducts in HIV patients as biomarkers of nevirapine haptenation upon bioactivation. The ultimate goal is to develop diagnostic methods for predicting the onset of nevirapine-induced toxic reactions.All included subjects were adults on nevirapine-containing antiretroviral therapy for at least 1 month. The protocol received prior approval from the Hospital Ethics Committees and patients gave their written informed consent. Nevirapine-derived adducts with the N-terminal valine of hemoglobin were analyzed by an established liquid chromatography-electrospray ionization-tandem mass spectrometry method and characterized on the basis of retention time and mass spectrometric fragmentation pattern by comparison with adduct standards prepared synthetically. The nevirapine adducts were detected in 12/13 patient samples, and quantified in 11/12 samples (2.58 ± 0.8 fmol/g of hemoglobin).This work represents the first evidence of nevirapine-protein adduct formation in man and confirms the ability of nevirapine to modify self-proteins, thus providing clues to the molecular mechanisms underlying nevirapine toxicity. Moreover, the possibility of assessing nevirapine-protein adduct levels has the potential to become useful for predicting the onset of nevirapine-induced adverse reactions.© 2012 Published by Elsevier Ireland Ltd.Abbreviations: cART, combined antiretroviral therapy; CID, collision-induced dissociation; GSH, glutathione; Hb, hemoglobin; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; 12-OH-NVP, 12-hydroxy-nevirapine; LC-ESI-MS/MS, liquid chromatography-electrospray ionization-tandem mass spectrometry; MHC, major histocompatibility complex; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine.* Corresponding author.

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Exploration of CYP450 and Drug Transporter Genotypes and Correlations with Nevirapine Exposure in Malawians

Cited by 25 publications

References 28 publications

Prevalence ofCYP2D6*4 1934G/A polymorphism in Western IndianHIVpatients

Prevalence ofCYP2D6*4 1934G/A polymorphism in Western IndianHIVpatients

Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

Evidence for nevirapine bioactivation in man: Searching for the first step in the mechanism of nevirapine toxicity

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