Artemisinin–a possible CYP2B6 probe substrate?

Asimus, Sara; Ashton, Michael

doi:10.1002/bdd.665

Cited by 11 publications

(4 citation statements)

References 30 publications

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“…AM demethylation activity was determined by measurement of the formation of DHA, according to the method of Asimus and Ashton (2009), with minor modifications. AM stock solution (50 mM) was prepared in CH 3 CN/H 2 O [50:50 (v/v)], and a working solution (500 M) was prepared by dilution of the stock solution in potassium phosphate buffer, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

Honda¹,

Muroi²,

Tamaki³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Artemether (AM) is one of the most effective antimalarial drugs. The elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters. The aim of this study was to identify cytochrome P450 (P450) isozymes responsible for the demethylation of AM and to evaluate functional differences between 26 CYP2B6 allelic variants in vitro. Of 14 recombinant P450s examined in this study, CYP2B6 and CYP3A4 were primarily responsible for production of the desmethyl metabolite dihydroartemisinin. The intrinsic clearance (V max /K m ) of CYP2B6 was 6-fold higher than that of CYP3A4. AM demethylation activity was correlated with CYP2B6 protein levels (P ‫؍‬ 0.004); however, it was not correlated with CYP3A4 protein levels (P ‫؍‬

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Section: Methodsmentioning

confidence: 99%

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

Honda¹,

Muroi²,

Tamaki³

et al. 2011

Drug Metab Dispos

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“…The CYP2B6 substrate selectivity comprises many diverse chemicals, including not only clinically used drugs but also many environmental chemicals such as pesticides (Turpeinen et al, 2006; Hodgson and Rose, 2007; Turpeinen and Zanger, 2012). Therapeutically important drugs metabolized primarily by CYP2B6 include the prodrug cyclophosphamide, which is converted to the direct precursor of the cytotoxic metabolites, phosphoramide mustard and acrolein, by 4-hydroxylation (Huang et al, 2000; Roy et al, 2005), the non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, which is 8-hydroxylated to become pharmacologically inactive (Ward et al, 2003; Desta et al, 2007), the atypical antidepressant and smoking cessation agent bupropion, which is converted to pharmacologically active hydroxybupropion (Faucette et al, 2000; Hesse et al, 2000; Turpeinen et al, 2005b), the anesthetics propofol (Court et al, 2001; Oda et al, 2001) and ketamine (Desta et al, 2012), the analgesic pethidine (meperidine; Ramírez et al, 2004); the μ-opioid receptor agonist, methadone (Totah et al, 2008), the antimalarial artemisinin (Svensson and Ashton, 1999; Asimus and Ashton, 2009), among numerous additional metabolic pathways of other drugs, to which CYP2B6 contributes in part, such as the antiretroviral, nevirapine (Erickson et al, 1999), and many others (Turpeinen and Zanger, 2012). Metabolic pathways suitable as probe for CYP2B6 activity include S-mephenytoin N -demethylation (Ko et al, 1998), bupropion hydroxylation (Faucette et al, 2000; Fuhr et al, 2007) and efavirenz, based on in vitro investigations (Ward et al, 2003; Desta et al, 2007).…”

Section: The Chemical Interaction Profile Of Cyp2b6mentioning

confidence: 99%

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

Zanger¹,

Klein²

2013

Front. Genet.

286

220

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Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4–12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems.

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“…Currently, CYP2B6 is estimated to metabolize, fully or partially, ~ 8-13% of clinically important drugs and a long list of other xenobiotics of toxicological relevance. 9,37 In addtion to efavirenz, other clinically important drugs for which CYP2B6 metabolic status is a major determinant of metabolism and response and/or toxicity include nevirapine, 38 methadone, 39 bupropion, 40 artemisinin, 41 and ketamine. 42 The metabolism of certain environmental pollutants 43 and pesticides 21 is also highly dependent on CYP2B6 metabolic status.…”

Section: Clinical Relevancementioning

confidence: 99%

PharmVar GeneFocus: CYP2B6

Desta

El‐Boraie

Gong

et al. 2021

Clin Pharma and Therapeutics

127

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The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP2B6 gene. Genetic variation within the CYP2B6 gene locus impacts the metabolism or bioactivation of clinically important drugs. Of particular importance are efficacy and safety concerns regarding: efavirenz, which is used for the treatment of HIV type‐1 infection; methadone, a mainstay in the treatment of opioid use disorder and as an analgesic; ketamine, used as an antidepressant and analgesic; and bupropion, which is prescribed to treat depression and for smoking cessation. This GeneFocus provides a comprehensive overview and summary of CYP2B6 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

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Artemisinin–a possible CYP2B6 probe substrate?

Cited by 11 publications

References 30 publications

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

PharmVar GeneFocus: CYP2B6

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