CYP2B6, CYP2A6 and UGT2B7 Genetic Polymorphisms are Predictors of Efavirenz Mid-dose Concentration in HIV-infected Patients
Identifieur interne : 000A41 ( Main/Exploration ); précédent : 000A40; suivant : 000A42CYP2B6, CYP2A6 and UGT2B7 Genetic Polymorphisms are Predictors of Efavirenz Mid-dose Concentration in HIV-infected Patients
Auteurs : Awewura Kwara [États-Unis] ; Margaret Lartey [Ghana] ; Kwamena W. C. Sagoe [Ghana] ; Ernest Kenu [Ghana] ; Michael H. Court [États-Unis]Source :
- AIDS (London, England) [ 0269-9370 ] ; 2009.
Descripteurs français
- KwdFr :
- Adulte, Aryl hydrocarbon hydroxylases (génétique), Benzoxazines (pharmacocinétique), Benzoxazines (sang), Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Femelle, Ghana, Glucuronosyltransferase (génétique), Génotype, Humains, Infections à VIH (génétique), Infections à VIH (sang), Infections à VIH (traitement médicamenteux), Inhibiteurs de la transcriptase inverse (pharmacocinétique), Inhibiteurs de la transcriptase inverse (sang), Mâle, Oxidoreductases, (N-demethylating) (génétique), Polymorphisme de nucléotide simple, Population d'origine africaine (génétique), Relation dose-effet des médicaments, Valeur prédictive des tests.
- MESH :
- génétique : Aryl hydrocarbon hydroxylases, Glucuronosyltransferase, Infections à VIH, Oxidoreductases, (N-demethylating), Population d'origine africaine.
- pharmacocinétique : Benzoxazines, Inhibiteurs de la transcriptase inverse.
- sang : Benzoxazines, Infections à VIH, Inhibiteurs de la transcriptase inverse.
- traitement médicamenteux : Infections à VIH.
- Adulte, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Femelle, Ghana, Génotype, Humains, Mâle, Polymorphisme de nucléotide simple, Relation dose-effet des médicaments, Valeur prédictive des tests.
English descriptors
- KwdEn :
- Adult, African Continental Ancestry Group (genetics), Aryl Hydrocarbon Hydroxylases (genetics), Benzoxazines (blood), Benzoxazines (pharmacokinetics), Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Dose-Response Relationship, Drug, Female, Genotype, Ghana, Glucuronosyltransferase (genetics), HIV Infections (blood), HIV Infections (drug therapy), HIV Infections (genetics), Humans, Male, Oxidoreductases, N-Demethylating (genetics), Polymorphism, Single Nucleotide, Predictive Value of Tests, Reverse Transcriptase Inhibitors (blood), Reverse Transcriptase Inhibitors (pharmacokinetics).
- MESH :
- chemical , blood : Benzoxazines, Reverse Transcriptase Inhibitors.
- chemical , genetics : Aryl Hydrocarbon Hydroxylases, Glucuronosyltransferase, Oxidoreductases, N-Demethylating.
- blood : HIV Infections.
- drug therapy : HIV Infections.
- genetics : African Continental Ancestry Group, HIV Infections.
- chemical , pharmacokinetics : Benzoxazines, Reverse Transcriptase Inhibitors.
- Adult, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Dose-Response Relationship, Drug, Female, Genotype, Ghana, Humans, Male, Polymorphism, Single Nucleotide, Predictive Value of Tests.
Abstract
UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study we determined whether selected
Mid-dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2–8 weeks of antiretroviral therapy.
The mean (±SD) mid-dose efavirenz plasma concentration was 3218 (±3905) ng/mL with coefficient of variation of 121%. Independent predictors of efavirenz concentration included
Our findings demonstrate independent effects of
Url:
DOI: 10.1097/QAD.0b013e3283319908
PubMed: 19779319
PubMed Central: 2875867
Affiliations:
- Ghana, États-Unis
- Massachusetts, Rhode Island, Région du Grand Accra
- Accra, Legon (Ghana)
- Université du Ghana
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Le document en format XML
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C." last="Sagoe">Kwamena W. C. Sagoe</name><affiliation wicri:level="3"><nlm:aff id="A2"> University of Ghana Medical School, Accra, Ghana</nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea> University of Ghana Medical School, Accra</wicri:regionArea><placeName><settlement type="city">Accra</settlement><region nuts="2">Région du Grand Accra</region></placeName></affiliation></author><author><name sortKey="Kenu, Ernest" sort="Kenu, Ernest" uniqKey="Kenu E" first="Ernest" last="Kenu">Ernest Kenu</name><affiliation wicri:level="3"><nlm:aff id="A3"> Korle-Bu Teaching Hospital, Accra, Ghana</nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea> Korle-Bu Teaching Hospital, Accra</wicri:regionArea><placeName><settlement type="city">Accra</settlement><region nuts="2">Région du Grand Accra</region></placeName></affiliation></author><author><name sortKey="Court, Michael H" sort="Court, Michael H" uniqKey="Court M" first="Michael H." last="Court">Michael H. Court</name><affiliation wicri:level="2"><nlm:aff id="A4"> Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea> Tufts University School of Medicine and Tufts Medical Center, Boston</wicri:cityArea></affiliation></author></analytic><series><title level="j">AIDS (London, England)</title><idno type="ISSN">0269-9370</idno><idno type="eISSN">1473-5571</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>African Continental Ancestry Group (genetics)</term><term>Aryl Hydrocarbon Hydroxylases (genetics)</term><term>Benzoxazines (blood)</term><term>Benzoxazines (pharmacokinetics)</term><term>Cytochrome P-450 CYP2A6</term><term>Cytochrome P-450 CYP2B6</term><term>Dose-Response Relationship, Drug</term><term>Female</term><term>Genotype</term><term>Ghana</term><term>Glucuronosyltransferase (genetics)</term><term>HIV Infections (blood)</term><term>HIV Infections (drug therapy)</term><term>HIV Infections (genetics)</term><term>Humans</term><term>Male</term><term>Oxidoreductases, N-Demethylating (genetics)</term><term>Polymorphism, Single Nucleotide</term><term>Predictive Value of Tests</term><term>Reverse Transcriptase Inhibitors (blood)</term><term>Reverse Transcriptase Inhibitors (pharmacokinetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Aryl hydrocarbon hydroxylases (génétique)</term><term>Benzoxazines (pharmacocinétique)</term><term>Benzoxazines (sang)</term><term>Cytochrome P-450 CYP2A6</term><term>Cytochrome P-450 CYP2B6</term><term>Femelle</term><term>Ghana</term><term>Glucuronosyltransferase (génétique)</term><term>Génotype</term><term>Humains</term><term>Infections à VIH (génétique)</term><term>Infections à VIH (sang)</term><term>Infections à VIH (traitement médicamenteux)</term><term>Inhibiteurs de la transcriptase inverse (pharmacocinétique)</term><term>Inhibiteurs de la transcriptase inverse (sang)</term><term>Mâle</term><term>Oxidoreductases, (N-demethylating) (génétique)</term><term>Polymorphisme de nucléotide simple</term><term>Population d'origine africaine (génétique)</term><term>Relation dose-effet des médicaments</term><term>Valeur prédictive des tests</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Benzoxazines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Aryl Hydrocarbon Hydroxylases</term><term>Glucuronosyltransferase</term><term>Oxidoreductases, N-Demethylating</term></keywords><keywords scheme="MESH" qualifier="blood" xml:lang="en"><term>HIV Infections</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>HIV Infections</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>African Continental Ancestry Group</term><term>HIV Infections</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Aryl hydrocarbon hydroxylases</term><term>Glucuronosyltransferase</term><term>Infections à VIH</term><term>Oxidoreductases, (N-demethylating)</term><term>Population d'origine africaine</term></keywords><keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Benzoxazines</term><term>Inhibiteurs de la transcriptase inverse</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Benzoxazines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="sang" xml:lang="fr"><term>Benzoxazines</term><term>Infections à VIH</term><term>Inhibiteurs de la transcriptase inverse</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à VIH</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Cytochrome P-450 CYP2A6</term><term>Cytochrome P-450 CYP2B6</term><term>Dose-Response Relationship, Drug</term><term>Female</term><term>Genotype</term><term>Ghana</term><term>Humans</term><term>Male</term><term>Polymorphism, Single Nucleotide</term><term>Predictive Value of Tests</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Cytochrome P-450 CYP2A6</term><term>Cytochrome P-450 CYP2B6</term><term>Femelle</term><term>Ghana</term><term>Génotype</term><term>Humains</term><term>Mâle</term><term>Polymorphisme de nucléotide simple</term><term>Relation dose-effet des médicaments</term><term>Valeur prédictive des tests</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Objective</title><p id="P1">UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study we determined whether selected <italic>UGT2B7</italic> polymorphisms could be used to enhance the prediction of efavirenz plasma concentrations from <italic>CYP2B6</italic> and <italic>CYP2A6</italic> genotypes.</p></sec><sec sec-type="methods" id="S2"><title>Methods</title><p id="P2">Mid-dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2–8 weeks of antiretroviral therapy. <italic>CYP2B6</italic> and <italic>CYP2A6</italic> genotypes had been previously reported. <italic>UGT2B7</italic> exon 2 SNPs c.735A>G (<italic>UGT2B7</italic>*1c; rs28365062) and c.802C>T (H268Y; <italic>UGT2B7</italic>*2; rs7439366) were determined by direct sequencing with <italic>UGT2B7</italic>*1a defined as the reference allele. Relationships between efavirenz plasma concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches.</p></sec><sec id="S3"><title>Results</title><p id="P3">The mean (±SD) mid-dose efavirenz plasma concentration was 3218 (±3905) ng/mL with coefficient of variation of 121%. Independent predictors of efavirenz concentration included <italic>CYP2B6</italic> c.516TT genotype (4,030 ng/mL increase; 95% CI, 2,882–5,505 ng/mL, <italic>P</italic><0.001), <italic>UGT2B7</italic>*<italic>1a</italic> carrier status (475 ng/mL increase; 95% CI, 138–899 ng/mL, <italic>P</italic>=0.004) and <italic>CYP2A6</italic>*<italic>9</italic> and/or *<italic>17</italic> carrier status (372 ng/mL increase; 95% CI, 74–742 ng/mL, <italic>P</italic>=0.013). Overall, <italic>CYP2B6</italic> c.516TT genotype, <italic>UGT2B7</italic>*1a carrier status and <italic>CYP2A6</italic>*<italic>9 or</italic> *<italic>17</italic> carrier status accounted for 45.2%, 10.1%, and 8.6% of the total variance, respectively.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">Our findings demonstrate independent effects of <italic>CYP2A6</italic> and <italic>UGT2B7</italic> genetic variation on efavirenz disposition beyond that of the <italic>CYP2B6</italic> polymorphisms. The development and testing of a pharmacogenetic algorithm for estimating the appropriate dose of efavirenz should incorporate genotypic data from both the oxidative and glucuronidation pathways.</p></sec></div></front></TEI><affiliations><list><country><li>Ghana</li><li>États-Unis</li></country><region><li>Massachusetts</li><li>Rhode Island</li><li>Région du Grand Accra</li></region><settlement><li>Accra</li><li>Legon (Ghana)</li></settlement><orgName><li>Université du Ghana</li></orgName></list><tree><country name="États-Unis"><region name="Rhode Island"><name sortKey="Kwara, Awewura" sort="Kwara, Awewura" uniqKey="Kwara A" first="Awewura" last="Kwara">Awewura Kwara</name></region><name sortKey="Court, Michael H" sort="Court, Michael H" uniqKey="Court M" first="Michael H." last="Court">Michael H. Court</name></country><country name="Ghana"><region name="Région du Grand Accra"><name sortKey="Lartey, Margaret" sort="Lartey, Margaret" uniqKey="Lartey M" first="Margaret" last="Lartey">Margaret Lartey</name></region><name sortKey="Kenu, Ernest" sort="Kenu, Ernest" uniqKey="Kenu E" first="Ernest" last="Kenu">Ernest Kenu</name><name sortKey="Sagoe, Kwamena W C" sort="Sagoe, Kwamena W C" uniqKey="Sagoe K" first="Kwamena W. C." last="Sagoe">Kwamena W. C. Sagoe</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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